Natural killer (NK) cells provide some of the earliest immune responses to infection, but when viruses manipulate or perturb the immune environment to alter NK cell function this places the host at a disadvantage. Indeed, others and we observe that in the context of HIV/SIV infection, although NK cells are not infected they can become dysfunctional over time. Several works have characterized protein and transcriptional profiles of NK cells during HIV/SIV infection, but none have examined whether the production of alternative transcripts and corresponding isoforms is modulated. This phenomenon occurs broadly in normal biology and in other disease states, and could provide a novel avenue of investigation that may yield better targets to restore or augment NK cell responses to HIV/SIV. Herein, we briefly summarize published and new data that may provide a perspective on how to target NK cell splice variants.