The appropriate discrimination between safe and dangerous situations and the subsequent decrease of fear expression in the presence of safety signals are crucial for survival and mental health. Learning of safety associations is often studied in terms of fear extinction, that is re-learning of a previously conditioned stimulus which is now no longer positively associated with danger. Numerous studies investigated neurobiological processes of fear extinction and provide a valid picture of the underlying neural structures and endocrine processes involved. However, a formerly neutral conditioned stimulus (CS) can also predict the non-occurrence of an aversive, potentially dangerous, unconditioned stimulus (US) from the very beginning and thus can serve as a safety stimulus. This process has been termed safety learning. Although safety learning has been known for almost a century, there has been little research on its underlying neurobiological mechanisms, in contrast to the more prominent Pavlovian fear conditioning and fear extinction. In this review, we propose that the well-known action of the hypothalamic neuropeptide oxytocin (OXT) in the regulation of fear and stress responses is complementary to safety learning. We summarize the literature focused on OXT signaling and safety learning in animals and humans, from the first studies of fear extinction and conditioned inhibition of fear to the most recent findings in molecular and behavioral research on initial social safety stimuli. At the end, we discuss the application of OXT as a therapeutic agent to psychopathologies related to deficits in safety learning.