This article looks back on the story of the Ambulatory Sentinel Practice Network (ASPN) and its successor, the National Research Network (NRN), through the eyes of its leaders during the first 40 years. Facilitated conversations over 2 years iteratively coalesced key facts and patterns in this collective account of what they had observed. Time-durable patterns observed are distilled for interpretation and application by contemporary practice-based research network (PBRN) leaders as they move forward. Looking back is done via developmental eras. The ASPN was proposed in 1978 as a set of change strategies for primary care research, ASPN gathered momentum through efforts of individuals, institutions, and small grants that mobilized enthusiasm and commitment in the face of headwinds. The network expanded into the research mainstream from 1988, addressing large socially important questions with greater acceptance and volume of PBRN research. The ASPN is now in an era of scaling up and adapting to huge technological, organizational, and business shifts and a growing emphasis on patient and community engagement, safety, and disparities. Archetypal dilemmas and balances that emerged and reemerged across these eras are distilled, along with ways they were addressed at the time. The authors then project their 40-year experience to future vistas they believe the PBRN value proposition can be adapted and extended; what they regard as promising directions future leaders to take.