The heterogeneity existing among cancer chemotherapeutic agents, even when structurally closely related, in their quantitative and qualitative interaction with the various cellular components of host defence mechanisms involved in cancer control is reviewed. In addition to being a possible determinant of antineoplastic drugs in vivo efficacy, this heterogeneity can be of importance also in the development of less empirical and more effective approaches to the design of combinations to be used in cancer chemoimmunotherapy. Nonspecific immunomodulatory agents are in fact also heterogenous in their mode of action on the various components of the immune complex. Examples of chemoimmunotherapeutic combinations based on drugs acting at complementary levels on host defences are presented and the mechanistic basis for their in vivo synergistic activity discussed.