Adherence to subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) requires both consistency with scheduled administration and persistence of therapy for a minimum of 3 years to achieve sustained long-term benefit. Reported adherence rates for both forms of allergen immunotherapy (AIT) have, in general, been low but have varied widely based on type of study, population, age, and setting. This chapter reviews adherence to AIT in “real life,” emphasizing studies that directly compare SCIT to SLIT. While nonpersistence for AIT varies from 11% to 97%, the mean for SCIT (54%) and SLIT (58%) is similar. Reported major reasons for discontinuation of SCIT include inconvenience, excessive time commitment, medical comorbidities, and financial concerns, while for SLIT they include lack of efficacy, adverse effects, inability to be compliant, and financial concerns. A multifaceted strategy involving shared decision-making, motivational interviewing, close follow-up, and engagement of the entire healthcare system is required to achieve adherence. Although there have been limited studies on cost-effectiveness, the data available on AIT in the United States demonstrate that reduced resource use and costs have improved in as little as 6 months; however, sustained cost-effectiveness depends on sustained adherence.