We use the non-homologous model of sensitization and kindling to help conceptualize processes occurring in the longitudinal course of bipolar disorder. The models help focus on the phenomena of episode recurrence, regression, and cycle acceleration occurring without medication and during treatment, when these progressive processes can re-emerge during tolerance development. The preclinical data suggest that it is the ratio of pathological versus adaptive factors mediated by changes in gene expression that mediate episode recurrence or suppression. During tolerance development, there may be selective loss of some episode-induced adaptive factors that may be re-engendered during a period off that medication. The models reveal long-term molecular changes induced by recurrent stresses, episodes of illness, and substances of abuse that can accumulate and lead to progressive increases in vulnerability to episode recurrence. The clinical and preclinical data converge in emphasizing the importance of prevention and early and sustained prophylaxis. New data also implicate brain-derived neurotrophic factor (BDNF) in genetic and environmental illness vulnerability and progression, as well as in the mechanisms of action of the mood stabilizers and antidepressants. Therapeutic agents may thus not only prevent recurrent affective episodes and their adverse consequences on the brain, behavior, and quality of life, but they may also be able to ameliorate the effects of stressors, and reverse or prevent some of the basic pathological brain mechanisms underlying illness progression.