This chapter is a monography concerning the possible role of tissue stiffness in the human carcinogenesis as well as its possible impact in the diagnosis, prognosis, and treatment of the malignancies. Cancer is a very serious health problem in mankind, with an increasing prevalence and incidence worldwide. Although in the last years, several diagnostic and therapeutic approaches were suggested and made available for managing human malignancies, the outcome of patients and their quality of life are still poor for most of these different forms of neoplasms (Torre LA, Siegel RL, Ward EM, Jemal A., Cancer Epidemiol Biomarkers Prev. 2016;25(1):16-27. doi: 10.1158/1055-9965.EPI-15-0578). Several reasons may explain this dismal prognosis: the aggressive biological behavior of some histological subtypes, the acute-, intermediate- or late- side effects of systemic chemotherapy and radiotherapy, including toxicity of organs, diarrhea, skin irritation, nausea, mucositis, alopecia, vomiting, intestinal discomfort, asthenia, the arising of immunosuppression with neutropenia, the increased risk of infections as well as the occurrence of secondary cancers, at variable time intervals, either within a few weeks or months/years after the end of anticancerous treatments. From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review). Int J Oncol.] 2019;54(2):407-419. doi: 10.3892/ijo.2018.4661). 1) Novel strategies and methodological approaches are strongly required to determine an effective improvement in the management of these diseases. It is conceivable to suppose that not only the genetic alterations, but also further important factors may be involved in determining the prognosis of patients, suffering from malignancies. 2) Extracellular matrix (ECM) represents a crucial and key component of tissue structure contributing to the initiation, growth, and progression of human carcinoma. This last consists of a three-dimensional and highly dynamic macromolecular network, supporting the structure of all mammalian cells and modulating their function. ECM is characterized by well-defined physical, biochemical and biomechanical properties and plays multiple functions, such as: a) the maintenance of cellular, tissue and organ homeostasis, b) the regulation of both the amounts and the activities of growth factors and receptors c) the preservation of an adequate hydration status and pH level in the tissue microenvironment. It undergoes a continuous but tightly regulated remodeling and several mechanisms participate in the control of its adequate composition and structural organization. Therefore, ECM regulates a wide series of distinct cell activities, such as differentiation, apoptosis, proliferation and migration as well as energy production and availability. In normal conditions, a dynamic interplay is established among mammalian cells and ECM, surrounding them. The result of this cooperation is the maintenance of a proper ECM composition, morphology, disposition and activity in all tissues and a correct intracellular structure and function, both in the cytoplasm and in micro-organelles, such as nucleus. In the last years, a large series of studies are focusing on a better understanding of ECM alterations and abnormalities, that emerge in its structure, shape and spatial organization, during the occurrence of different pathological conditions, such as inflammation and cancer. 3) ECM contributes to regulate and modulate a wide series of distinct cell activities, such as differentiation, apoptosis, proliferation, and migration as well as energy production and availability. In normal conditions, a dynamic interplay is established among mammalian cells and ECM, surrounding them. It involves soluble factors, such as chemokines, cytokines, costimulatory molecules, additional biological mediators (oxidants and prostaglandins) and physical stimuli (microenvironment stiffness and tensional/compression forces). The result of this cooperation is the maintenance of a proper ECM composition, morphology, disposition and activity in all tissues and a correct intracellular structure and function, both in the cytoplasm and in micro-organelles, such as nucleus. In the last years, a large series of studies are focusing on a better understanding of ECM alterations and abnormalities, that emerge in its structure, shape and spatial organization, during the occurrence of different pathological conditions, such as inflammation and cancer. To date, some studies are investigating the mutual interactions among the cells, that are progressively acquiring a cancerous phenotype, and the stroma surrounding them as well as the changes in physical properties of nucleus- and cytoplasmic- microenvironment. It has been shown that the ability of malignant cells to grow and to metastasize depends on several factors, such as the relationship occurring between the stroma stiffness as well as the nucleus and cytoplasm rigidity. Since 2003, Professor Donald Ingber published some interesting papers about tensegrity and tissue stiffness as a possible risk factor for cancer development (Ingber DE. Tensegrity I. Cell structure and hierarchical systems biology. ] J Cell Sci. 2003;116(Pt 7):1157-73; Ingber DE. Tensegrity II. How structural networks influence cellular information processing networks] J Cell Sci. 2003;116(Pt 8):1397-408). He has shed new light on this topic. Taking advantage from these experimental evidences, this paper describes the state of the art concerning this topic and the diagnostic, therapeutic and prognostic use in clinical practice in the last years as well as the possible future application of these evidences. We performed this chapter to identify the available studies, assessing: 1) the possible association between tissue stiffness and risk of cancer development; up to now a rather high number of malignant tumoralhistotypes have been identified in the different human organs and have been included in our anatomopathological classifications. Therefore, we decided to consider in our review only the following organs: brain, breast, colon, esophagus, kidney. liver, lung, prostate, stomach, thyroid and uterus and for each of them we have analyzed the most frequent, aggressive and lethal malignancies as paradigm; 2) the "state of art" for this topic with clinical (diagnostic and therapeutic management) purpose; 3) the potential relationship between the values of tissue stiffness and prognosis in patients with cancers involving the above reported organs and the current use as well as their potential future application in clinical practice.