Pharmacotherapy includes a growing number of clinically effective medications for substance use disorder, yet there are significant barriers to its adoption and implementation in routine clinical practice. The Medication Research Partnership (MRP) was a successful effort to promote adoption of pharmacotherapy for opioid and alcohol use disorders in nine substance abuse treatment centers and a commercial health plan. This qualitative analysis of interviews (n = 39) conducted with change leaders at baseline and at the end/beginning of 6-month change cycles explains how treatment centers overcame obstacles to the adoption, implementation, and sustainability of pharmacotherapy. Results show that barriers to adopting, implementing, and sustaining pharmacotherapy can be overcome through incremental testing of organizational change strategies, accompanied by expert coaching and a learning community of like-minded professionals. The greatest challenges lie in overcoming abstinence-only philosophies, establishing a business case for pharmacotherapy, and working with payers and pharmaceutical representatives.