Bipolar disorder is one of the most severely debilitating of all medical illnesses. It can lead to significant suffering for patients and their families, limit functioning and workplace productivity, and with its risks of increased morbidity and mortality, it is increasingly recognized as a major public health problem. For a large number of patients, outcomes are poor. Patients with bipolar disorder generally experience high rates of relapse, a chronic recurrent course, lingering residual symptoms, functional impairment, psychosocial disability and diminished well-being. Despite this, little is known about the specific pathophysiology of bipolar disorder. A better understanding of the neurobiological underpinnings of this condition, informed by preclinical and clinical research, will be essential for the future development of specific targeted therapies that are more effective, achieve their effects more quickly and are better tolerated than currently available treatments. An abundance of research has implicated specific neuroendocrine, neurotransmitter and intracellular signaling systems in the pathophysiology and treatment of this illness. More recently, genetic association studies have identified numerous genes that confer vulnerability to the disorder, many of which are known to function in the signaling pathways previously identified as relevant to the etiology of the illness. In this article, we will review current knowledge regarding the neurotransmitter systems, signaling networks, neuroendocrine systems and genetics of bipolar disorder; all of these allow insight into the mechanism of illness and thus offer potential novel directions for the development of novel therapeutics.