Natural killer (NK) cell education is an evolving concept first used to describe the reactivity setpoint of an individual NK cell and, more recently, the composition of the NK cell repertoire in each person. The terms “education,” “tuning,” and “disarming” have each been used to describe how NK cells achieve “missing self” responsiveness—the ability to eliminate target cells lacking normal levels of self human leukocyte antigen (HLA) class I molecules. NK cell function extends beyond “missing self” reactivity, however, and includes antibody-dependent cell-mediated cytotoxicity, adaptation, and memory. Each of these functions is influenced by an NK cell’s affinity for self-HLA class I molecules. The killer immunoglobulin like receptors (KIR) that engage HLA molecules are polymorphic, and the gene loci for KIR and HLA segregate independently; hence, even closely related individuals may have different compound KIR/HLA genotypes that govern their NK cell education. In addition to KIR, an array of activating and inhibitory receptors co-expressed on each NK cell not only varies its ability to engage with transformed, infected, or damaged cells but also generates an assortment of signals whose integration dictates response. Furthermore, organization of the NK receptors and the cytoskeleton at the immunological synapse distinctly impact activation and tolerance, revealing the architectural underpinnings of activation threshold. We discuss NK cell education in this broadened context, focusing on the mechanisms that establish and adjust cellular function and highlighting how NK cell education influences human health and disease.