This review explores the incessant evolutionary interaction and co-development between immune system evolution and somatic evolution, to put it into context with the short, over 60-year, detailed human study of this extraordinary protective system. Over millions of years, the evolutionary development of the immune system in most species has been continuously shaped by environmental interactions between microbes, and aberrant somatic cells, including malignant cells. Not only has evolution occurred in somatic cells to adapt to environmental pressures for survival purposes, but the immune system and its function has been successively shaped by those same evolving somatic cells and microorganisms through continuous adaptive symbiotic processes of progressive simultaneous immunological and somatic change to provide what we observe today. Indeed, the immune system as an environmental influence has also shaped somatic and microbial evolution. Although the immune system is tuned to primarily controlling microbiological challenges for combatting infection, it can also remove damaged and aberrant cells, including cancer cells to induce long-term cures. Our knowledge of how this occurs is just emerging. Here we consider the connections between immunity, infection and cancer, by searching back in time hundreds of millions of years to when multi-cellular organisms first began. We are gradually appreciating that the immune system has evolved into a truly brilliant and efficient protective mechanism, the importance of which we are just beginning to now comprehend. Understanding these aspects will likely lead to more effective cancer and other therapies.