BACKGROUND: Fusions are increasingly pursued as oncology therapeutic targets. The current study evaluated differences in outcomes for fusion versus nonfusion targets. METHODS: Outcomes were compared for patients with fusions versus those with other alterations for US Food and Drug Administration-approved single agents (from package inserts) and for patients treated at the University of California at San Diego. RESULTS: A total of 28 drugs approved by the US Food and Drug Administration (6189 patients) were included in the analysis. The median response rate was 68% versus 50% for fusions versus nonfusion matches (odds ratio [OR], 1.67; P < .0001); solid tumor therapies had an OR of 2.07 (P < .0001) and hematologic therapies had an OR of 3.35 (P < .0001) for fusion versus nonfusion targets. The University of California at San Diego analysis included 79 patients in whom fusions were treated of the 2455 patients screened. Patients matched to fusions were found to have a longer median progression-free survival (PFS) (11.6 months; 95% CI, 4.0-35.4 months) compared with those unmatched to fusions (4.9 months; 95% CI, 3.5-8.8 months) (P = .034). Patients with fusions matched to other alterations present in the tumor had a median PFS that was indistinguishable from that of those patients with fusions who were treated with unmatched therapy (4.0 months vs 5.0 months; P = .75). CONCLUSIONS: Significantly higher response rates and a longer PFS were observed when targeting fusions compared with nonfusions. The observations reported in the current study suggest that fusions are important targets and that additional studies are needed to confirm that optimized therapy may require targeting fusions, even in the presence of other alterations.