BACKGROUND KIT‐directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT‐mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun‐damaged (CSD) melanoma. Dasatinib has superior preclinical activity in comparison with other tyrosine kinase inhibitors against cells with the most common KIT mutation, exon 11L576P. The ECOG‐ACRIN E2607 trial assessed dasatinib in patients with these melanoma subtypes. METHODS Patients received 70 mg of oral dasatinib twice daily. The primary objective for this 2‐stage phase 2 trial was response rate. Stage I was open to KIT+ and wild‐type KIT (KIT–) mucosal, acral, and CSD melanoma (n = 57). Stage II accrued only KIT+ tumors (n = 30). To enrich the trial for KIT+ tumors, vulvovaginal melanoma was added, and CSD melanoma was removed from eligibility. Secondary objectives included progression‐free survival (PFS), overall survival (OS), and safety. RESULTS From May 2009 to December 2010, the first stage enrolled 57 patients. Among the evaluable patients, 3 of 51 (5.9%) achieved a partial response: all were KIT–. Stage II closed early because of slow accrual (November 2011 to December 2015). In stage II, 4 of 22 evaluable patients (18.2%) had a partial response; the median duration was 4.2 months. The median PFS was 2.1 months (n = 73; 95% confidence interval CI, 1.5‐2.9 months). The median OS was 7.5 months (95% CI, 6.0‐11.9 months). In exploratory analyses, no differences were seen in PFS or OS with the KIT status or subtype. Dasatinib was discontinued because of adverse events in 9 of 75 patients (12%). CONCLUSIONS The dasatinib response rate among KIT+ melanoma patients was low. In view of its clinical activity, it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma. Cancer 2017;123:2688‐97. © 2017 American Cancer Society. In this multicenter, cooperative‐group, 2‐stage, single‐arm clinical trial, 7 of 73 evaluable patients (9.6%) with mucosal, acral, vulvovaginal, or chronically sun‐damaged melanoma achieved a partial response (wild‐type KIT, 3 of 42; KIT mutation, 4 of 25; and unknown KIT status, 0 of 6). The dasatinib response rate among KIT‐mutant melanoma patients is lower than anticipated.