The use of antidepressants (ADs) in bipolar disorder (BD) is controverted. Even though ADs are generally not recommended as a first-line treatment in BD, they are often used in clinical practice. Antidepressants’ risk/benefit ratio varies among individuals, with no absolute contraindications posed. Some evidence has demonstrated a potential risk associated with their use for manic or hypomanic switch and also rapid cycling, mixed episodes, and, lastly, an increased suicide risk, especially in BD type I. In patients with bipolar depression and mixed features, the use of ADs might worsen the course of illness. This chapter will discuss the evidence available on the use of ADs in BD, with a focus on specific clinical situations in which AD use might confer a higher risk of adverse outcomes and should be avoided.