Profiling gene expression in the addicted brain has revealed both agent-specific and common drug-induced neural adaptations, providing valuable insights for the understanding of the relevant molecular and cellular mechanisms. The development of transcriptome-based sequencing analysis has equipped us with potent tools that can be combined with neuroscience tools and approaches including the isolation of particular regions, circuits, and cells involved in addiction, genetic models including artificially selected strains and humans varying in vulnerability and response, and interventional models including pharmacological challenges and gene-based manipulations of pathway function and response. These approaches will further enable us to deconstruct the transcription machinery and epigenetic regulation in the addicted brain.