Natural killer (NK) cells recognize targets stressed by malignant transformation 
or infection and can be long-lived. They become educated by interacting with 
major histocompatibility antigen (MHC) class I molecules to gain function to 
kill targets and produce cytokines. In the clinic, haploidentical NK cells can 
be adoptively transferred to treat cancer. Persistence and in vivo expansion of 
NK cells depends on lymphodepleting chemotherapy to make space and induce 
release of endogenous IL-15. In vivo expansion is also enhanced by cytokine 
administration but IL-2 has the down side of stimulating CD25hi regulatory T 
cells (Tregs). Other limitations to NK-cell therapy include poor in vivo 
survival and lack of specificity. Bispecific or trispecific killer engagers that 
target CD16 on NK cells to enhance recognition of tumor antigens, and 
desintegrin and metalloproteinase 17 (ADAM17) inhibition that prevents CD16 
shedding after NK-cell activation should promote enhanced killing of cancer with 
specificity. These are exciting times; more than 35 years after NK cells were 
initially described, we are exploiting their capacity for clinical therapy.