The present text provides a review of waterborne as well as dietary copper (Cu) toxicity and Cu homeostasis in fish, and leads to suggestions for further research in this area. Copper, although essential for life, is a potent toxicant and as such, delicate homeostatic controls have evolved at the organismal and cellular level. During exposure to elevated levels of Cu in the water or the diet, homeostatic systems may become overwhelmed such that cellular Cu levels increase to a point where protein function becomes impaired. A range of potential cellular targets for Cu manifest in altered physiology and toxicity, at the organ and organismal level during Cu exposure; these targets and organismal responses are discussed. Copper toxicity is not simply a matter of ambient concentrations as water chemistry greatly influences not only the bioavailability of this metal but also the physiology and thus susceptibility of fish. This complexity has recently been realized and is being considered in current environmental regulations for Cu. Prolonged exposure to Cu elicits an acclimation response which includes a compensatory response of the functions impaired by Cu and adjustments in the homeostatic control of the metal, enabling fish to survive despite continued exposure and to tolerate subsequent exposures to higher concentrations. Although not quantified, these acclimation responses must occur at a cost to the organism, possibly explaining observations of reduced growth, reproductive output, and swimming performance. The literature review forming the basis for this chapter was completed by December 2010.