From 2005 to 2015, the publication of noninferiority trials increased by six-fold. Noninferiority trials assess whether a new treatment's efficacy is comparable with that of the standard of care and have several appeals. Noninferiority trials can evaluate for both noninferiority and superiority of a new treatment. In addition, multiple treatment modalities exist, and new treatments may be advantageous for reasons beyond efficacy. Common elements of trial design such as the research question, outcomes, statistical analysis, and interpretation of results differ meaningfully between noninferiority trials and superiority trials. The noninferiority margin, constancy assumption, and assay sensitivity are unique aspects of noninferiority trials. As with all randomized controlled trials, patient engagement in and reporting of noninferiority trials are also important. In this review, we discuss the methodological considerations and limitations of noninferiority trials.