Manganese (Mn) is an essential metal that is responsible for several physiological functions, including proper immune function, bone growth, digestion, reproduction, energy metabolism and antioxidant defences. However, excessive exposure to this metal can result in an irreversible condition known as “manganism”, a disease that primarily results in Parkinsonian-like symptomatology. Although the mechanisms by which Mn is absorbed into the digestive tract are not completely clear, a number of uptake mechanisms have been identified on the surface of enterocytes. These include import of Mn2+ via the divalent metal transporter 1 (DMT1) and uptake of Mn3+ via complexation with the protein transferrin (Tf). Upon entering the blood, Mn is distributed diffusely throughout the body, with the brain, bone, kidneys and liver acquiring the highest accumulation. A variety of transporters regulate Mn import, including DMT1 or Tf-Tf receptor internalization, choline transporter, citrate transporter, voltage-gated and store-operated calcium channels, and the zinc transporters ZIP8/14. Recent findings suggest a role for the magnesium transporter HIP14 and the P-type transmembrane ATPase ATP13A2 in Mn uptake across cellular membranes. Mn serves as an important cofactor for many enzymes that are key in regulating general cellular function. Intracellular buffering mechanisms also include preferential sequestration within mitochondria. Finally, Mn export has yet to be fully understood, but new evidence points to the iron exporter ferroportin as a potential exporter. This chapter will address the various processes associated with maintenance of optimal Mn levels and the consequences of improper Mn homeostasis.