As Web 2.0 and social media make the communication landscape increasingly participatory, empirical evidence is needed regarding their impact on and utility for health promotion. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched 4 medical and social science databases for literature (2004-present) on the intersection of Web 2.0 and health. A total of 514 unique publications matched our criteria. We classified references as commentaries and reviews (n = 267), descriptive studies (n = 213), and pilot intervention studies (n = 34). The scarcity of empirical evidence points to the need for more interventions with participatory and user-generated features. Innovative study designs and measurement methods are needed to understand the communication landscape and to critically assess intervention effectiveness. To address health disparities, interventions must consider accessibility for vulnerable populations.