The ability to identify, develop, and exploit conditions of safety and security is central to survival and mental health, but little is known of the neurobiology of these processes or associated positive modulations of affective state. We studied electrophysiological and affective correlates of learned safety by negatively correlating an auditory conditioned stimulus (CS) with aversive events (US). This CS came to signify a period of protection, reducing fear responses to predictors of the US and increasing adventurous exploration of a novel environment. In nonaversive conditions, mice turn on the CS when given the opportunity. Thus, conditioned safety involves a reduction of learned and instinctive fear, as well as positive affective responses. Concurrent electrophysiological measurements identified a safety learning-induced long-lasting depression of CS-evoked activity in the lateral nucleus of the amygdala, consistent with fear reduction, and an increase of CS-evoked activity in a region of the striatum involved in positive affect, euphoric responses, and reward.