The popularity of smokeless tobacco (ST), or noncombusted tobacco, usually placed within the mouth to be chewed, sucked, or swallowed, is growing rapidly and its prevalence of use is rising globally, due (in part) to greater convenience, as allowable cigarette smoking areas are rapidly decreasing, and increased social acceptability. Though data are limited, ST usage has been directly linked to a number of adverse health outcomes. The potential role that immune dysfunction, including dysregulation of immune cells and their components, may play in the progression of these adverse health outcomes is only just beginning to emerge. Evidence suggesting reproductive outcomes, such as perinatal mortality, preterm birth, and reduced sperm viability, also exists in conjunction with ST use. Cardiovascular health may also be impacted by ST use, resulting in increased blood pressure and endothelial dysfunction, both of which may potentially lead to cardiovascular diseases. This review describes the toxicological implications associated with ST use, with emphasis on immune, reproductive, and cardiovascular outcomes. Epidemiological studies are discussed with respect to experimental studies to help develop the relationship between ST and disease pathology. This review also summarizes the gaps in ST knowledge and potential future directions that are needed to more fully delineate the complex systems driving the adverse health outcomes associated with its use.