Natural killer (NK) cells’ origin in mice and humans. In both species, natural killer (NK) cells have their cellular origin in oligopotent common lymphoid progenitor cells (CLPs). (A) In mice, NK precursors (NKP) evolve into mature NK (mNK) cells through a 6-stage process, in which they acquire the expression of specific activating and inactivating receptors. CLP cells develop from hematopoietic stem cells (HSCs). CLPs then give rise to Pro-B cells, innate lymphoid cells (ILCs), Pre-T cells (L-Ti) and CD122+ Pre-T/early NKP lineages within the murine bone marrow. The transition of NKPs into committed immature NK cells (iNK) is marked by the expression of NKG2D (stage 1), followed by the expression of NK1.1 and NCR1 (stages 2 and 3). iNKs differentiate into mNKs, acquiring the expression of CD51, DX5, CD43 and CD11b (stages 4 and 5). Finally, mNKs migrate into secondary lymphoid organs (stage 6). (B) In humans, CLPs also suffer differentiation to originate mNKs through a complex process in which differential and sequential regulation of key surface receptors takes place. CD122 (IL2Rβ) sets the fate of CLPs into the NK lineage. The resultant NKPs then differentiate into mNKs, which can be divided into different subpopulations. These subpopulations of mNK cells are defined by the acquisition and differential expression of CD16 and/or CD56. This process ultimately gives origin to CD56dim/-CD16bright NK cells and to CD56bright CD16dim NK cells, the most common NK cells in humans (around 90% and 10%, respectively).