The last decade has seen the emergence of immunomodulators as therapeutic agents in cancer treatment. Interleukins (ILs) are a category of small cell-signaling molecules that organize communication and interaction between immune cells and therefore they could be used as perfect immunomodulators. IL-12 is a promising candidate for cancer immunotherapy since it plays a major role in development of antitumor immune response. Numerous studies report that IL-12 promotes an effective destruction of cancer cells both in vivo and in vitro. In addition, IL-12 has anti-angiogenic activity and it is able to dramatically decrease tumor-supportive activities of tumor-associated macrophages. The first part of the review is devoted to immunobiology of IL-12. Signaling pathways of IL-12 as well as clinical trials of this cytokine are discussed. The second part of the review is concerned on the inherited variations in IL-12A and IL-12B genes that could modulate cancer susceptibility, and as a consequence, possess predictive, therapeutic, or prognostic significance. It is known that functional single nucleotide polymorphisms (SNPs) in IL-12A and IL-12B genes may dramatically affect on protein expression level, or alter its functions, which may lead to immune disorders, autoimmune diseases, and eventually contribute to cancer occurrence. The list of genetic polymorphisms for further investigations might include the following: IL-12B_+1188A/C (rs3212227), IL-12A_+277G/A (rs568408), IL-12A_-798T/A (rs582054), IL-12A_-504T/G (rs190533), IL-12A_-1148T/C (rs2243123), and IL-12B_+16974 A/C. Perhaps, some of these SNPs may become an attractive target for oncogenomics and possibly could be used in programs of early cancer diagnosis as well as cancer prevention in the nearest future.