Few animal models address the characteristics of the longitudinal course of bipolar disorder. However, behavioral sensitization (to recurrent stressors and psychomotor stimulants) and kindling of seizures both provide clues to mechanisms in the progressive course of bipolar disorder.We describe aspects of bipolar illness that show sensitization and kindling-like increases reactivity to the recurrence of stressors, mood episodes, and bouts of substance abuse. Mechanisms of these events and clinical implications for treatment are discussed.Early life stress is a risk factor for the development of episodes of unipolar depression and bipolar disorder and the acquisition of substance abuse. Initial affective episodes are often triggered by the recurrence of psychosocial stressors in adulthood, but after many episodes have occurred, episodes may also begin to emerge spontaneously in a kindling-like progression. More prior episodes are associated with faster recurrences, dysfunction, disability, frontal cortical abnormalities, cognitive impairment, shorter telomeres, treatment refractoriness, and an increased risk of a diagnosis of dementia in old age. Sensitization to stressors, episodes, and substances of abuse each appear driven by epigenetic mechanisms and their accumulation on DNA, histones, and microRNA. Patients with bipolar illness in the USA are more ill than those from Europe and experience more sensitization to stressors, episodes, substance abuse, as well as more genetic vulnerability across four generations.The sensitization and kindling models highlight the importance of early intervention and prevention in order to limit or halt the downhill progression of bipolar disorder and its multiple comorbidities toward treatment refractoriness. Clinical data support this conclusion as well but have not been sufficient to change practice in the direction of early intervention. It is hoped that a better understanding of sensitization and kindling-like mechanisms will add neurobiological rationales for the importance of prevention and sustained prophylactic intervention in rendering bipolar disorder a more benign illness.