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Smoking remains one of the most significant public health challenges globally, disproportionately affecting vulnerable populations such as individuals with lower socioeconomic status, adolescents, women, racial and ethnic minorities, and those living with mental health conditions. Despite widespread awareness of its adverse health effects, including respiratory disease, cardiovascular disease, and various cancers, smoking persists within these groups due to a complex interplay of individual, social, and structural factors. Barriers such as financial instability, limited education, systemic discrimination, targeted tobacco marketing, and restricted access to cessation resources further exacerbate this vulnerability. This chapter explores the intricate relationship between smoking and vulnerability, highlighting the role of systemic inequities and social determinants of health in shaping smoking behavior. It emphasizes the urgent need for tailored public health interventions, culturally sensitive cessation programs, and policy measures such as increased taxation and restrictions on targeted advertising. By addressing both behavioral and structural drivers, this chapter aims to illuminate actionable strategies to reduce smoking prevalence, advance health equity, and mitigate the profound impact of tobacco use among vulnerable populations.