The ability to recognize and properly respond to instances of protection from impending danger is critical for preventing chronic stress and anxiety-central symptoms of anxiety and affective disorders afflicting large populations of people. Learned safety encompasses learning processes, which lead to the identification of episodes of security and regulation of fear responses. On the basis of insights into the neural circuitry and molecular mechanisms involved in learned safety in mice and humans, we describe learned safety as a tool for understanding neural mechanisms involved in the pathomechanisms of specific affective disorders. This review summarizes our current knowledge on the neurobiological underpinnings of learned safety and discusses potential applications in basic and translational neurosciences.