Medication nonadherence (MNA) after solid organ transplantation is highly prevalent and associated with (late) (sub)clinical acute rejection, graft dysfunction and graft loss, development of donor-specific anti-HLA antibodies, and antibody-mediated rejection. MNA is predominantly unintentional and originates from barriers to adherence that are often multifactorial and complex. Tools to establish an early diagnosis of MNA include incorporation of MNA as a vital sign in daily clinical practice, self-reporting using validated questionnaires, calculating intrapatient variability in drug exposure and applying electronic monitoring, and recent audio and video technologies such as in home telemonitoring. MNA is a modifiable risk factor after organ transplantation, and treatment is most effective if a multimodal approach is used. Management of MNA comprises education (cognitive) and counseling (behavioral) that require the involvement of a trained multidisciplinary team [ideally physician, nurse (specialist), social worker, transplant coordinator, psychologist, clinical pharmacist], electronic reminder and support systems (eg, Medication Event Monitoring System, smartphone), and different types of novel mobile health applications as well as simplification of the medication dosing regimen. Future studies that evaluate novel therapeutic approaches for MNA should assure the use of reliable MNA measures, focus on multimodal individualized therapy for enriched nonadherent target populations (eg, adolescents), and incorporate clinically relevant endpoints. Costs, time, and personnel investments should be taken into account when assessing scalability and cost-effectiveness of novel therapeutic strategies. This review provides suggestions how different types of transplant centers can set up a dedicated MNA program according to available resources to define and achieve realistic clinical goals in managing MNA.