In selecting and adapting medications to treat the specific clinical features of a patient with bipolar disorder (BPD) over time, a foundation strategy is to have good working knowledge of up-to-date practice guidelines. The World Federation of Societies of Biological Psychiatry Guidelines has the reasoned advantage of weighing safety/tolerability as high as efficacy. Most successful treatments for BPD start to separate from placebo within 1 week; most differences between regimens occur within the first 4 weeks. This observation extrapolates to a strategy of discontinuing or adding a second drug for symptoms unimproved within 1 month of treatment initiation. The weight of evidence argues against starting treatment with combination regimens, despite evidence that over time most patients do receive combination drug regimens and appear to tolerate them well. The current design paradigm for adjunctive trials generally strongly weights trials in favor of the sponsor drug. Well managed, BPD is often compatible with fully good health, both symptomatically and functionally. Consequently, for whatever regimens are found to accomplish excellent symptom control, it is important to achieve regimens that are well tolerated by all bodily systems. This chapter emphasizes the tactics needed to accomplish this specific to individual medications. The chapter also addresses the serious, broad failure of pharmaceutical companies to develop new drugs with novel mechanisms for BPD therapy and proposes a series of steps that might reenergize drug development to the benefit of psychiatrists and patients alike.