The mammalian olfactory system is intertwined with emotional and memory centers of the brain, thus providing an ideal model to study olfactory-based fear conditioning, a behavior lying at the intersection of perception, emotion, and cognition. In the present chapter, we first outline a brief overview of the olfactory system’s anatomy, and then, we define the structural and functional changes induced by aversive olfactory conditioning with a clear focus on rodent and human models. In detail, we discuss aversive experience-dependent modulations at each level of the olfactory pathway, differentiating between experimentally presented (shock) and naturally occurring aversive pairings (toxicosis). Whenever possible, developmental trajectories are reported. The description of aversive olfactory conditioning mechanisms are finally used to provide insights on psychiatric and medical conditions characterized by aversive odor memories which may open up future possibilities of developing novel treatment options.