Genetically engineered rodents can be used to examine the influence of single genes on alcoholism-related phenotypes. We review studies that employed gene targeting with a focus on ethanol withdrawal-associated behaviors. Earlier studies targeted the glutamate and GABA systems as contributors to the underlying hyperexcitable state of convulsions or similar signs of ethanol withdrawal. Over the past decade, many gene-targeting studies have continued to focus on the glutamatergic and GABAergic systems; however, an increasing number of these studies have focused on other withdrawal outcomes such as anxiety-like behavior and escalated ethanol consumption. Although negative affective states may drive escalated ethanol drinking, few reported studies examined the phenotypes together. However, there is significant overlap in the systems that were manipulated in relation to studying the phenotypes individually. These studies reveal common genetic influences on withdrawal-associated anxiety, convulsions, and escalated drinking that may contribute to relapse, setting the stage for the identification of novel medications to jointly target these effects.