Cancer is one of the most prominent causes of mortality in children and adults causing about 9 million deaths annually, is a major health problem world-wide. The transformation of normal cells to cancer cells may arise due to dysregulation of oncogenes, tumour suppressers and/or stability genes. These transformed cells are sensed by the cells of the immune system, especially T cells, through specific receptors for an effective immune response. But unfortunately even after the interaction with T cells, an effective immune response is not generated. Considering the importance of costimulation in the regulation of immune responses against relapsed cancer, the manipulation of this pathway to increase immunity, regress the growth, augment the expression of pro-apoptotic molecules and induce the apoptosis of lymphomas represents a potential therapeutic approach. This novel strategy of costimuilation activation/inhibition can be effectively exploited to develop immunotherapy either using humanised antibodies against CD80, CD86 and CD40 or CD28 fusogenic proteins for the treatment of intracellular pathogens like M. tuberculosis, HIV, L donovani, T cruzi, etc. This strategy can also be used as an alternative strategy or in combination with the drugs. Since this approach is based on modulating the immune system of the hosts rather than targeting the pathogen; hence it significantly diminishes chance of emergence of drug resistant strains of pathogens and if applied properly, may overcome the rising menace of infectious diseases. The potent role of costimulatory molecules is aptly established in the optimum activation of T cells and APCs; the cells that play a cardinal role in curbing the infections. Hence, immunotherapy involving costimulatory molecules can be a breakthrough strategy to treat various diseases, minimising side effects inflicted by drug therapies and in restricting the emergence of drug resistance.