This chapter presents a series of treatment algorithms which may be used as a general guide in sequencing treatment so that patients who fail to respond to first-line conventional treatment may still achieve a substantial amelioration of depressive syndromes or recurrences. Depression in most treatment-resistant bipolar patients can usually be adequately treated. The authors have been able to model the loss of efficacy via tolerance to the anticonvulsants carbamazepine, lamotrigine, diazepam, and valproate in the model of amygdala-kindled seizures. The incidence of clinical tolerance development to lamotrigine in the affective disorders and dose regimens most likely to prevent this occurrence require further observation and study. With the availability of a large number of putative treatment agents within each class of drug for bipolar illness (mood stabilizers, antidepressants, and antimanics) appropriate sequencing and management of complex drug combinations may be fraught with difficulty, but at the same time potentially life-saving.