The ability of the myocardium to successfully compensate for and adapt to environmental stress ultimately determines whether the heart will decompensate and fail or maintain preserved function. Despite the importance of the myocardial response to environmental stress, very little is known with respect to the biochemical mechanisms that are responsible for mediating and integrating the stress response in the heart. In the present review we summarize recent experimental material suggesting that the cytokines expressed within the myocardium in response to environmental injury, namely tumor necrosis factor (TNF), interleukin-1 (IL-1), and the interleukin-6 (IL-6) family, play an important role in initiating and integrating homeostatic responses. However, these stress-activated cytokines all have the potential to produce cardiac decompensation when expressed at sufficiently high concentrations. Accordingly, the theme to emerge from this review is that the short-term expression of stress-activated cytokines within the heart may be an adaptive response to stress, whereas long-term expression of these molecules may be frankly maladaptive by producing cardiac decompensation.