The underlying pathophysiology of bipolar disorder is a continually evolving complexity of multilayer interacting and independent systems. The dearth of adequate preclinical or clinical models that incorporate the various features of the illness, i.e., acute and chronic, recurrent and episodic, and time-course and treatment-related variables, has made the consistency and interpretation of data difficult. Newer technologies and the availability of structurally and mechanistically distinct pharmacologic agents have expanded opportunities for experimental study. In addition to the well-known neurotransmitter systems that are disrupted in mood disorders, critical guanine nucleotide-binding protein (G protein)-coupled signaling pathways are implicated in modulating mood state. Regulation of gene expression and identification of factors regulating neuroplasticity and neurotrophic events in the central nervous system in bipolar disorder are 2 of the more recent approaches contributing to clarification of the pathophysiology and potential treatment options.