The physiological responses to stressors, including hormonal profiles and associated tissue responsiveness have been extensively studied in teleosts, but the molecular mechanisms associated with this adaptive response are not well understood. The advent of cDNA microarray technology has transformed the field of functional genomics by revealing global gene expression changes in response to stressor exposures even in non-mammalian vertebrates, including fish. A unifying response in studies related to stressor exposure is activation of the hypothalamus-pituitary-interrenal (HPI) axis in fish, leading to cortisol release into the circulation. Here we will discuss the implications of some of the gene expression changes observed in response to acute stress in fish, while highlighting a role for cortisol in this adaptive stress response. As liver is a key organ for metabolic adjustments to stressors and also is a major target for cortisol action, the genomic studies pertaining to stress and glucocorticoid regulation have focused mainly on this tissue. The studies have identified several genes that are altered transiently after an acute stressor exposure in fish. A number of these stress-responsive genes were also modulated by glucocorticoid receptor activation, suggesting that elevation in cortisol levels during stressor exposure may be a key signal for target tissue molecular programming, essential for stress adaptation. The identification of regulatory gene networks that are stress activated, and modulated by cortisol, both in hepatic and extra-hepatic tissues, including gonads, brain, immune cells and gills, will provide a mechanistic framework to characterize the multifaceted role of cortisol during stress adaptation.