The role of withdrawal-related phenomena in the development and maintenance of alcohol addiction remains under debate. A ‘self-medication’ framework postulates that emotional changes are induced by a history of alcohol use, persist into abstinence, and are a major factor in maintaining alcoholism. This view initially focused on negative emotional states during early withdrawal: these are pronounced, occur in the vast majority of alcohol-dependent patients, and are characterized by depressed mood and elevated anxiety. This concept lost popularity with the realization that in most patients, these symptoms abate over 3–6 weeks of abstinence, while relapse risk persists long beyond this period. More recently, animal data have established that a prolonged history of alcohol dependence induces more subtle neuroadaptations. These confer altered emotional processing that persists long into protracted abstinence. The resulting behavioral phenotype is characterized by excessive voluntary alcohol intake and increased behavioral sensitivity to stress. Emerging human data support the clinical relevance of negative emotionality for protracted abstinence and relapse. These developments prompt a series of research questions: (1) are processes observed during acute withdrawal, while transient in nature, mechanistically related to those that remain during protracted abstinence?; (2) is susceptibility to negative emotionality in acute withdrawal in part due to heritable factors, similar to what animal models have indicated for susceptibility to physical aspects of withdrawal?; and (3) to what extent is susceptibility to negative affect that persists into protracted abstinence heritable?