While implementation of the Patient Protection and Affordable Care Act brings significant opportunities for safety net providers (SNP), local systems vary in how well they adapt to the rapidly evolving environment. Collaboration may enhance SNP capacity to leverage opportunities in the health reform era. Our study examines key opportunities and challenges SNPs face under health reform and how providers use collaboration as a strategy to adapt to the new environment. A qualitative study of 78 executives at safety net organizations identified six priorities that pose both opportunities and challenges for SNP, and around which collaboration is used as a strategy to achieve common goals: Medicaid expansion, outreach and enrollment, capacity and access, health system transformation, health insurance exchanges, and reductions in government funding. Three types of collaborations emerged: policy and advocacy, community action, and practice-based. Types of collaborations and stakeholders involved appeared to vary by priority.