ABSTRACT Housing First is an evidence-based intervention designed to house individuals who are chronically homeless and are experiencing serious mental illness. The cross-sector collaboration required to provide person-centred supports to this population has resulted in increased understanding of Housing First as a whole systems response. Housing First implementation acts as a catalyst for systems change, yet research on how this change occurs is limited. This study examined the role of regional networks in advancing systems change through Housing First. A qualitative, multiple case study was conducted to examine two multi-city networks established by community leaders in the Canadian homelessness sector. Data collection activities included document analysis, interviews (n = 10), and two follow-up focus groups. Thematic analyses were conducted for each network, followed by a cross-case analysis. Findings indicate that engaging in a multi-city network increases leaders’ collective capacity to create conditions for change and to advance and sustain systems-level changes.