This chapter focuses on the crucial issue of compliance and adherence with treatment in healthcare, particularly among patients with chronic illnesses. It explores the multifaceted nature of nonadherence, involving patients, healthcare providers, and the healthcare system. It emphasizes the importance of patient-provider partnerships and the involvement of patients in treatment decisions to achieve optimal care outcomes. The World Health Organization (WHO)’s definition of adherence is presented, along with evidence showing the negative impacts of poor adherence on quality of life, safety, and healthcare costs. It explores various factors that influence nonadherence, such as socioeconomic factors, healthcare system issues, physician-related factors, and patient-related factors like mental health and health literacy. The chapter also addresses condition-related and therapy-related factors, such as complex medication regimens and side effects. Strategies to tackle adherence challenges are proposed, encompassing patient engagement, education, simplified treatment plans, consideration of social determinants of health, mental health support, and effective communication techniques.