Historical controls are an attractive approach to clinical trials for a number of reasons, including the potential for a study sample size that is smaller than needed for a parallel group randomized trial. The key objectives of the clinical trial should be kept in mind, however, when considering study design, including choice of control. This includes whether the study results need to be regarded as sufficiently rigorous to support the desired study conclusions. Clinical trials intended to provide rigorous answers to questions of drug effect are designed to support the assumption that the study comparator group was not meaningfully different from the treated group at the start of the treatment period. There are a number of circumstances that have the potential to cause a difference between the historical control and the treatment group that can influence the study endpoint that will be discussed. There are also factors that can increase confidence in the appropriateness of a historical control comparison that will be discussed.