Computer-mediated communication (CMC), and specifically social media, may affect the mental health (MH) and well-being of its users, for better or worse. Research on this topic has accumulated rapidly, accompanied by controversial public debate and numerous systematic reviews and meta-analyses. Yet, a higher-level integration of the multiple disparate conceptual and operational approaches to CMC and MH and individual review findings is desperately needed. To this end, we first develop two organizing frameworks that systematize conceptual and operational approaches to CMC and MH. Based on these frameworks, we integrate the literature through a meta-review of 34 reviews and a content analysis of 594 publications. Meta-analytic evidence, overall, suggests a small negative association between social media use and MH. However, effects are complex and depend on the CMC and MH indicators investigated. Based on our conceptual review and the evidence synthesis, we devise an agenda for future research in this interdisciplinary field.