Objective: Exercise is effective in producing a wide range of beneficial health outcomes. To ensure safe and effective exercise, guidance has been developed for seemingly healthy people and for people with a single disease. Unfortunately, similar guidance is not yet available for people with comorbidity in addition to the index disease or for people with multimorbidity. However, researchers have recently started to explore the application of exercise in people with comorbidity or multimorbidity, and these innovative applications of exercise have produced encouraging results: Exercise was shown to be safe and effective. The objective of the present article is to identify the underlying principles of exercise in people with comorbidity or multimorbidity. Method: We perform a narrative review of applications of exercise in people with comorbidity or multimorbidity. Results: Principles of exercise in people with comorbidity or multimorbidity appear to include (a) a rigorous assessment of health status, (b) the adaptation of exercise to comorbidity or multimorbidity, (c) the application and integration of behavior change techniques into the exercise plan, and (d) clinical reasoning to support the application of exercise by health professionals. Conclusions: We posit that these 4 principles provide a framework for the successful development of exercise guidance for people with comorbidity or multimorbidity.