Patients with uncommon malignancies (incidence less than 6 cases per 100,000 persons per year) are frequently understudied at the level of genomic targets. Researchers expected that, like common cancers, uncommon cancer patients would benefit from FDA-approved anticancer medications in doses greater than their approved label. In the Drug Rediscovery Protocol (DRUP), individuals with therapy-refractory metastatic cancers whose molecular profile is actionable are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy.Patients are enrolled in two parallel cohorts based on their tumor type, molecular profile, and study drug. The primary endpoint is clinical benefit (complete response, partial response, stable disease at least 16 weeks). Of the 1,145 cases considered, 500 individuals (164 of whom had rare malignancies) received one of the 25 available medicines and were assessable for treatment outcome. In both the uncommon cancer and nonrare cancer subsamples, the overall clinical benefit rate was 33%. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P≤0.001) or BRAF inhibitors (9% vs. 1%; P≤0.001). Patients with rare cancer treated with small-molecule BRAF inhibitors experienced greater rates of clinical benefit (75%) than the nonrare cancer subgroup. Comprehensive molecular testing in individuals with uncommon malignancies may provide similar therapeutic possibilities and clinical benefit to those with typical cancers. The work emphasizes the significance of access to broad molecular tests in ensuring equal care opportunities for all cancer patients.