Gene expression changes resulting from cocaine abuse in both humans and animal models have been studied for several decades. Although human studies have been very useful at illuminating cocaine-related expression changes, there are many factors complicating these studies, including the difficulty of obtaining high-quality postmortem brain tissue and patient comorbidities. Animal models of cocaine abuse have served as valuable additions to human data and allow examination of specific aspects of cocaine abuse, including immediate early gene expression and the molecular effects of abstinence and relapse. In total, human and animal studies of cocaine abuse have uncovered gene expression changes in the brain related to a number of molecular functions, including the extracellular matrix, synaptic communication and neuroplasticity, receptors, ion channels and transporters, oligodendrocytes and myelin, apoptosis and cell death, mitochondrial function, signal transduction, and transcription factors. In addition, the mitogen-activated protein kinase and synaptic long-term potentiation signal transduction pathways are highlighted as pathways in which multiple components are altered by cocaine. Pathways and processes affected by changes in gene expression that overlap among multiple species may be promising pharmacotherapeutic targets for reducing the behavioral effects of cocaine abuse and the relapse potential observed in humans.