Behavioral interventions are typically studied with the use of a conventional between-subject randomized controlled trial (RCT) design. In this design, the effect of an intervention on one group of patients is compared with the effect of a control condition on another group of patients, such that a between-subject change is tested. A between-subject design has an underlying assumption that there is a homogenous treatment effect for a behavioral intervention, drug, or psychotherapy and that the way the intervention operates in the study will tend to operate in the same way in many other patients. We review some of the philosophical and practical problems with the use of this design when a clinician is attempting to decide on a course of behavioral treatment aimed at within-subject change in patients who are likely to have heterogeneous or unique responses to behavioral treatment. We also review the biases inherent in our current clinical practice model, which does not use any empirical data collection or design for testing if a treatment is useful, and also in the conventional between-subject personalized medicine RCT designs. We propose increased use of single-patient (also known as N-of-1) trials that employ within-subject designs, in cases where treatment response is heterogeneous – as is the case for most psychological and behavioral treatments. Limitations of such designs include that they can only be used when the treatment is potentially reversible, the patient can act as their own control, and the outcome can be measured repeatedly. Increased use of within-subject trials may address in many more instances the more clinically relevant question of how a specific patient will respond to a specific treatment and could introduce a more harmonious scientific approach into the way we treat our patients. We have incorporated a case presentation that illustrates the complexities of applying evidence drawn from these different designs to selecting and evaluating treatments for the behavioral issues commonly faced by clinicians and patients.