The literature on corticotropin (ACTH) regulation of cortisol secretion, effects of nicotine on plasma cortisol and ACTH levels, and the cortisol response to smoking cessation is reviewed. A dose-dependent increase in plasma cortisol levels is found in habitual smokers after smoking two cigarettes. Nicotine mediates this response via a central mechanism to release cortisol from the adrenal cortex. The sites of action of nicotine appear to be in the hypothalamus or brain stem. Complete cessation of smoking is followed by a fall in plasma cortisol levels that is associated with the withdrawal of the nicotine stimulus. In addition, anxiety levels increase and plasma epinephrine levels decrease. Nicotine withdrawal symptoms confront smokers who want to quit. Many of the symptoms seem to be related to the body's response to changes in cortisol levels. As part of a comprehensive smoking cessation program, one or two intramuscular injections of ACTH gel have been shown to help smokers stop and continue to abstain from smoking.