This article reviews the agents used to treat manic patients. It has been suggested that up to 20 percent of all manic patients are refractory to lithium. We reviewed studies suggesting that drugs affecting the serotoninergic, adrenergic, dopaminergic, and opioid neurotransmission systems, as well as anticonvulsants and others, are possible alternative treatments. Despite the large number of agents used, few large controlled studies carefully examine these interventions. Clinical assessments using specific manic rating scales are lacking in most studies. Among the successful alternative treatments reported, carbamazepine has received the most intensive research. Other suggested therapeutic agents, such as levothyroxine and clorgyline, require additional research to verify their effectiveness. From these pharmacological approaches and an understanding of pathophysiology of mania, future therapeutic interventions can be formulated.