This chapter examines the potential sites of action of toxicants on corticosteroid signaling, mostly based on information gathered from literature on mammalian models. In bony fishes, corticosteroids are secreted from the interrenal tissues (analogous to the adrenal cortex) located in the head kidney region. Cortisol stimulation is implicated in a wide array of whole animal changes including osmo- and iono-regulation, respiration, immune responses, reproduction, growth, and metabolism. The chapter presents molecular and biochemical information on the fish corticosteroid receptor (CR), which shows characteristics similar to mammalian CR. The chapter summarizes information on CR signaling and key steps that may be sensitive to direct toxicant impact. The chapter also identifies possible pathways/molecules that may be indirectly involved in CR signaling and sensitive to contaminant impact. Fish corticosteroid receptor summarizes binding studies that have established the receptor characteristics of the glucocorticoid receptor and the mineralocorticoid receptor of CRs in fish.