Abstract Manganese (Mn) is an essential element for humans, animals, and plants. In humans and animals the systemic Mn status is regulated by homeostatic mechanisms. The natural presence of Mn and its compounds in the environment is being progressively overridden by anthropogenic enrichment. The main sources of Mn exposure are occupational, including mining, iron/steel making, ferro/silico-Mn alloy and dry alkaline battery production, and welding. Environmental Mn exposure is lower and is usually related to industrial emissions, the use of Mn compounds in agriculture and as fuel additives, and a high Mn content in drinking water. A high content of Mn in milk formula, in total parenteral nutrition solution, and in drugs of abuse, as well as iron deficiency, can also increase the Mn body burden. Besides through increased absorption, systemic Mn overload can derive from impaired biliary excretion due to hepatic insufficiency. The main toxic effects of Mn are on the central nervous system, including impairment of motor and cognitive function. Manganism is a neurological disorder that may occur in response to high inhalation exposures in occupational settings and which is characterized by mood changes and an extrapyramidal syndrome resembling Parkinson disease. Prolonged exposure to lower Mn doses can lead to an increased frequency of the signs of parkinsonism. Effects on the respiratory, reproductive, cardiovascular, hematological, endocrine, and immunological systems are also discussed in this chapter, including genotoxicity and carcinogenicity.