In addition to surgery, radiotherapy, chemotherapy, and targeted therapy, immunotherapy is now the fifth pillar of oncology treatment. Despite this status, determinants of immunotherapy response in most tumors are still unknown. One phenotype that was hypothesized to enhance immunogenicity is microsatellite instability (MSI), or the accumulation of errors in repetitive sequences due to loss of function of mismatch repair (MMR) genes. To test this hypothesis, Le et al1 treated 41 patients with colorectal and other cancers with the anti–programmed cell death protein 1 (PD-1) checkpoint inhibitor pembrolizumab and determined that patients whose tumors harbored MSI were more likely to respond. Building on these results, Le et al2 conducted a phase 2 trial of pembrolizumab in patients whose advanced solid tumors harbored MSI (86 patients representing 12 different tumor histologic types). The objective response rate was 53%, and complete responses were achieved in 21% of patients. Based on those results, in 2017, the US Food and Drug Administration granted approval for pembrolizumab for the treatment of solid tumors harboring MSI—the first tumor-agnostic oncology drug approval.