Antibacterial combinations have long been used to accomplish a variety of therapeutic goals, including prevention of resistance and enhanced antimicrobial activity. In vitro synergy testing methods, including the checkerboard array, the time-kill study, diffusion assays, and pharmacokinetic/pharmacodynamic models, are used commonly in the research setting, but are not routinely performed in the clinical microbiology laboratory because of test complexity and uncertainty about their predictive value for patient outcomes. Optimized synergy testing techniques and better data on the relationship between in vitro results and clinical outcomes are needed to guide the rational use of antimicrobial combinations in the multidrug resistance era.