The association between computer-mediated communication (CMC) and well-being is a complex, consequential, and hotly debated topic that has received significant attention from pundits, researchers, and the media. Conflicting research findings and fear over negative outcomes have spurred both moral panic and further research into these associations. To create a more comprehensive picture of trends, explanations, and future directions in this domain of research, we conducted a systematic meso-level review of 366 studies across 349 articles published since 2007 that report associations between CMC and well-being. Although most of this research is not explicitly theoretical, several potential theoretical mechanisms for positive and negative effects of CMC on well-being are utilized. The heterogeneity of effects in the studies we reviewed could be explained by the discipline in which the research is conducted, the methodology used, the types of CMC and well-being examined, and the population studied. Our evaluation of this body of research highlights the importance of attending to how we conceptualize communication and well-being, the questions we ask, and the populations and contexts we study when both reading and producing research on CMC and well-being.