Extant evidence indicates that individuals with bipolar disorder (BD) are differentially affected by overweight/obesity and abdominal obesity. Excess weight is associated with a more complex illness presentation, non-recovery, and recurrence. Herein, we sought to review literature describing the effects of structured individualized physical exercise on disparate neurobiological substrates implicated in the pathophysiology of BD. We conducted a PubMed search of all English-language articles published between 1966 and July 2008 with BD cross-referenced with the following search terms: exercise, neurobiology, pathophysiology, pathoetiology, brain, cognition, neuroplasticity, and neurodegeneration. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. Contemporary models of disease pathophysiology in BD implicate disturbances in cellular resilience, plasticity, and survival in the central nervous system. Individualized exercise interventions are capable of alleviating the severity of affective and cognitive difficulties in heterogeneous samples. It is posited that exercise is a pleiotropic intervention that engages aberrant neurobiological systems implicated in metabolism, immuno-inflammatory function, and cellular respiration. Structured exercise regimens exert a salutary effect on interacting networks mediating metabolism, immuno-inflammatory function, and cellular respiration. In keeping this view, buttressed by controlled evidence describing robust anti-depressant effects with exercise (e.g., public health dose), a testable hypothesis is that structured exercise is capable of improving psychiatric and somatic health in BD.