Alcohol and psychoactive substance use are major contributors to global morbidity and mortality and present significant challenges in insurance medicine. This chapter provides an overview of definitions, classification systems, and global epidemiology, along with diagnostic frameworks and risk stratification approaches. It examines health and behavioral risks associated with alcohol, opioids, stimulants, sedatives, hallucinogens, inhalants, cannabis, and synthetic or novel psychoactive substances (NPS). In addition, the chapter addresses performance-enhancing drugs (PEDs), including anabolic-androgenic steroids, other hormonal agents, and nonhormonal enhancers. While not traditionally classified as substances of abuse, PEDs carry important implications for underwriting risk assessment. Practical tools such as screening methods, laboratory testing, and consideration of risk modifiers are discussed. Underwriting strategies are illustrated through case examples, offering guidance for evaluating complex scenarios involving substance use or enhancement. By integrating clinical evidence, population-level data, and practical assessment techniques, this chapter provides a structured framework for medical directors and underwriters to evaluate substance-related risks in life insurance.