The diagnostic possibilities entertained in the critical care unit are limited in number versus other noncritical care settings. However, diagnostic errors are common. A major consequence of diagnostic errors concerns drug therapy decisions. Specifically, diagnostic errors not only lead to wasteful and unnecessary treatments, but may also subject the patient to potentially serious deleterious effects, for example from exposure to toxic medications, delay in treatment, or failure in treating the correct underlying condition. A significant cause leading to diagnostic errors implicates faulty clinical reasoning due to cognitive factors. This chapter introduces sound clinical reasoning and provides a no-nonsense approach to common clinical presentations in the ICU. Additionally, a collaborative, team-based approach to diagnosis is proposed with pharmacists playing an active role.