Although the memory capacity of innate immune cells, termed trained immunity (TI), is a conserved evolutionary trait, the cellular and molecular mechanisms involved are incompletely understood. One fundamental question is whether the induction of TI generates a homogeneous or heterogeneous population of trained cells. In this issue of the JCI, Zhang, Moorlag, and colleagues tackle this question by combining an in vitro model system of TI with single-cell RNA sequencing. The induction of TI in human monocytes resulted in three populations with distinct transcriptomic profiles. Interestingly, the presence of lymphocytes in the microenvironment of monocytes substantially impacted TI. The authors also identified a similar population of monocytes in various human diseases or in individuals vaccinated with bacillus Calmette-Guérin. These insights warrant in-depth analysis of TI in responsive versus nonresponsive immune cells and suggest that modulating TI may provide a strategy for treating infections and inflammatory diseases.