Bipolar disorder as it is currently treated in the community and in academic settings is associated with a surprisingly high-degree morbidity and treatment resistance. While some of this poor outcome may be due to inherent difficulties of the illness itself, much of the difficulty appears attributable to less than optimal pharmacotherapeutic approaches and patient education about the illness. We emphasize the conceptualization of the illness progressing in an untoward direction, driven by several types of sensitization mechanisms, each involving epigenetic changes. Epigenetics refers to environmentally- induced chemical changes in DNA, histones, and micro RNA structure and function which endure in a long-lasting fashion. This potential for accumulating epigenetic marks from recurrent stressors, episodes and bouts of substance abuse speaks to the importance of early and consistent long term pharmacoprophylaxis starting after a first episode of mania in order to prevent illness progression. We review the emerging evidence for a new recommendation for ultraintensive treatment after a first manic episode and the wealth of data indicating the importance of having lithium involved in the treatment regimen. Problems of bipolar illness morbidity and treatment resistance are particularly pronounced in the United States (USA). Compared to many European countries, bipolar illness in the USA appears to have an earlier age of onset, run a more difficult course, and have more psychiatric and medical comorbidities. This greater complexity of illness typically requires not monotherapy as is often recommended, but complex combination therapy with multiple medications targeting multiple symptoms and pathways. If instituted judiciously, the use of more medications can lead not only to better efficacy, but also, contrary to convention wisdom, fewer side effects. It is hoped that reconceptualization of bipolar illness as a progressive one that can undergo malignant transformation if not adequately treated will help lead to revisions in conventional treatment practices that will render the illness more benign it its long-term outcome.