Copper is an essential dietary element. Because of its potent redox activity and high affinity for biomolecules, cellular copper metabolism has been traditionally regarded as a series of protein shuttles to a final destination buried deep within protein active sites to prevent toxicity. Several decades of evidence have now established exogenous copper as a modulator of cell signaling, demonstrating that copper can serve as a signal itself and can potentiate or block signaling at multiple points in subcellular and intercellular signal transduction pathways. More recently, emerging evidence shows that copper is an important endogenous regulator of cell signaling, through mobilization of labile metal ions from existing cellular stores, which can affect diverse processes including cell proliferation, tumorigenesis, and neurotransmission. This chapter will describe the current state of knowledge on the role of copper in signal transduction with a focus on mechanisms mediated by direct copper interactions with cellular targets.