With advances in medical care, youth with chronic illness have the potential for higher quality of life; however, these treatments often come with cost (i.e., burden, financial) that can result in non-adherence. Pediatric non-adherence, on average, is approximately 50% across chronic health conditions. Research has identified effective, evidence-based assessment measures and intervention strategies to promote regimen adherence in youth. Yet, these measures and strategies typically are designed for clinical trials and thus may not be feasible or practical in typical clinic settings. As the field of adherence assessment and intervention expands, it will be important to devise evidence-based tools that are pragmatic and can be translated easily into practice. To guide this future direction, the goals of this paper are to review evidence-based adherence assessment and intervention strategies that can be used with youth and families in clinical practice, to illustrate the complexities of addressing adherence concerns in routine practice, and to discuss the challenges of disseminating and implementing evidence-based strategies in the real world.