BACKGROUND: Innovations and improvements in care delivery are often not spread across all settings that would benefit from their uptake. Scale-up and spread efforts are deliberate efforts to increase the impact of innovations successfully tested in pilot projects so as to benefit more people. The final stages of scale-up and spread initiatives must contend with reaching hard-to-engage sites. OBJECTIVE: To describe the process of scale-up and spread initiatives, with a focus on hard-to-engage sites and strategies to approach them. DESIGN: Qualitative content analysis of systematically identified literature and key informant interviews. PARTICIPANTS: Leads from large magnitude scale-up and spread projects. APPROACH: We conducted a systematic literature search on large magnitude scale-up and spread and interviews with eight project leads, who shared their perspectives on strategies to scale-up and spread clinical and administrative practices across healthcare systems, focusing on hard-to-engage sites. We synthesized these data using content analysis. KEY RESULTS: Searches identified 1919 titles, of which 52 articles were included. Thirty-four discussed general scale-up and spread strategies, 11 described hard-to-engage sites, and 7 discussed strategies for hard-to-engage sites. These included publications were combined with interview findings to describe a fourth phase of the national scale-up and spread process, common challenges for spreading to hard-to-engage sites, and potential benefits of working with hard-to-engage sites, as well as useful strategies for working with hard-to-engage sites. CONCLUSIONS: We identified scant published evidence that describes strategies for reaching hard-to-engage sites. The sparse data we identified aligned with key informant accounts. Future work could focus on better documentation of the later stages of spread efforts, including specific tailoring of approaches and strategies used with hard-to-engage sites. Spread efforts should include a "flexible, tailored approach" for this highly variable group, especially as implementation science is looking to expand its impact in routine care settings.