Despite the HIV "test-and-treat" strategy's promise, questions about its clinical rationale, operational feasibility, and ethical appropriateness have led to vigorous debate in the global HIV community. We performed a systematic review of the literature published between January 2009 and May 2012 using PubMed, SCOPUS, Global Health, Web of Science, BIOSIS, Cochrane CENTRAL, EBSCO Africa-Wide Information, and EBSCO CINAHL Plus databases to summarize clinical uncertainties, health service challenges, and ethical complexities that may affect the test-and-treat strategy's success. A thoughtful approach to research and implementation to address clinical and health service questions and meaningful community engagement regarding ethical complexities may bring us closer to safe, feasible, and effective test-and-treat implementation.