The brain, arguably the most complex organ of the body, plays a critical role in the predisposition, expression and maintenance of alcoholism. This adds an unmatched degree of complexity in the search for the causes of alcoholism as compared to other illnesses with a genetic component such as type 2 diabetes. The brain orchestrates such processes as cognition, emotion, mood, learning and motivation through circuits in a network of different brain regions which communicate through synaptic connections. Synaptic communication is spatially and temporally mediated by the cellular expression of genes, regulation of the expression of these genes and the functioning of the corresponding proteins. However, how individual differences, influenced by genetic variation, affect synaptic communication and functional plasticity of alcohol-sensitive brain circuits is not well understood. This is a burgeoning research area which holds promise for psychiatric research in general (Akil et al., 2010; Koob and Volkow, 2010). Over the last several decades a great deal of work has examined the consequences of alcohol exposure on the plasticity of the brain. A parallel line of work has begun to uncover the genes and genetic variation that might contribute to or mediate alcohol-induced plasticity. This volume contains critical reviews of the current state of these research domains: Functional plasticity and genetic variation; which we hope will offer novel insights into the neurobiology of alcoholism. The first chapter discusses the newly identified role of microRNAs in the neuronal mechanisms of alcohol tolerance and the potential involvement in other alcohol phenotypes. The use of Drosophila in understanding the genetics of alcohol-related phenotypes is then reviewed followed by a chapter on neural plasticity, human genetics and risk for alcohol dependence. In the next two chapters approaches to understanding alcoholism via examination of gene expression are reviewed. The first of these (Farris et al.,) is a comprehensive review of the powerful use of expression genetics to study the neurobiology of alcoholism, while the second (Bjork et al.,) highlights the need to examine gene expression alterations in clinically relevant animal models of alcoholism. The final chapter in this section reviews progress in the identification of genes for alcohol phenotypes in mice. The second half of the volume changes gears with chapters focusing on the cellular and synaptic consequences of alcohol-induced plasticity in specific brain regions. The first of these reviews glutamate plasticity in the amygdala followed by a chapter on ethanol action on dopamine neurons of the ventral tegmental area. The prefrontal cortex and striatum are covered in the next two chapters. Finally, synaptic plasticity at Purkinje neurons in the cerebellum is reviewed. In summary, this volume has highlighted two important areas in alcohol research which have significantly increased our understanding and given us an appreciation for the complexity of alcoholism as a brain disease. We hope this volume will begin to stimulate some convergence between these areas.