Drugs targeting immune checkpoint molecules such as CTLA-4, PD-1, and PD-L1 are being heralded as a breakthrough in oncology. However,“breakthrough” is a misnomer belying several decades of basic immunology advances and clinical trial and error leading up to this point. It was only after basic science uncovered the protean pathways restraining anti-tumor immunity that we could begin to unravel how to subvert them. The broad activity spectrum of PD-1 pathway blockers against multiple cancer types has validated this as a “common denominator” treatment approach and dispels the perception that “immunogenic” cancers are anomalies. We are now challenged to understand immune resistance mechanisms utilized by “non-responsive” tumor types (eg, prostate cancer) as well as the 50% or more of individuals with “responsive” tumor types who do not benefit from these drugs. Identifying collateral pathways for co-targeting in combination treatment regimens requires an intellectual leap to consider unexpected intersections between the immune system and genetics, epigenetics, and metabolism. For instance, tumor mutational density, a surrogate indicator of neo-antigens available for immune recognition, correlates with the responsiveness of melanoma to anti-CTLA-4, and lung cancer to anti-PD-1. In the final analysis, teamwork with cross-fertilization of ideas across different scientific disciplines has driven the evolution to today’s “breakthroughs” and will meet tomorrow’s challenges.