One of the most important traits of immune host defense against pathogens is memory, which improves survival if the same pathogen is reencountered. However, immune memory can also be deleterious, driving autoimmune diseases and the rejection of transplanted organs. Memory characteristics have been considered a fundamental property of adaptive immune cells such as T and B lymphocytes (1). However, innate immune cells such as myeloid cells and natural killer (NK) cells can also adapt to previous encounters with pathogens through epigenetic, transcriptional, and functional reprogramming, called trained immunity (2). The discovery of this innate immune memory emerged from studies with live vaccines and was described as being largely nonspecific (3). On page 1122 of this issue, Dai et al. (4) reveal that monocytes and macrophages acquire specific memory and induce organ rejection in mice, which could be prevented to improve transplantation outcomes.