Although recent studies have shown that chromium (as the trivalent ion) is not an essential trace element, it has been demonstrated to generate beneficial effects at pharmacologically relevant doses on insulin sensitivity and cholesterol levels of rodent models of insulin insensitivity, including models of type 2 diabetes. The mode of action of Cr(III) at a molecular level is still an area of active debate; however, the movement of Cr(III) in the body, particularly in response to changes in insulin concentration, suggests that Cr(III) could act as a second messenger, amplifying insulin signaling. The evidence for the pharmacological mechanism of Cr(III)’s ability to increase insulin sensitivity by acting as a second messenger is reviewed, and proposals for testing this hypothesis are described.