IO has witnessed a long history of highs and lows. Although conventional cytokines and vaccine immunotherapies were approved for certain cancers, high toxicities, low efficacy and conflicting evidence limited their widespread adoption. Jaideep V. Thottassery and Nidhi Dhingra at SmartAnalyst reveal how the discovery of the first checkpoint protein CTLA4, and approval of ipilimumab, a CTLA4-blocking antibody for melanoma, lay down the foundation for modern-day IO.