The long-standing dogma that immunological memory is the exclusive prerogative of the adaptive immune system has been challenged by emerging evidence that innate immunity can also maintain memory of past events. Such immunological imprinting takes two forms, trained innate immunity and tolerance. Trained immunity involves metabolic and epigenetic adaptations in innate immune cells and their progenitors in the bone marrow upon exposure to certain microbial and/or inflammatory stimuli so that the “trained” cells would be poised to respond much faster and stronger to a subsequent challenge (e.g., a new infection that is not necessarily the same as the earlier one). Conversely, tolerance leads to attenuated immune responses to secondary stimuli. This review focuses on trained immunity and discusses evidence for its existence from lower organisms to humans, its mechanistic underpinnings, and its translational ramifications. Although trained immunity can be considered as an evolutionarily conserved beneficial response against reinfections, in the setting of modern societies with high prevalence of chronic mucosal and systemic inflammatory diseases, trained immunity could also promote maladaptive immune responses that aggravate pathology. Thus, depending on context, innate immune memory could be therapeutically manipulated using defined agonists to either promote innate immune responses (particularly useful for the treatment of infections or chemotherapy-induced myelosuppression) or suppress excessive inflammation in inflammatory and autoimmune diseases.