Natural killer cells are innate effector cells of the immune system, believed to limit viremia and tumor burden before the onset of adaptive T and B cell immunity (1, 2). This task is met by an increase of NK cells in peripheral blood 3–5 days after infection or tumor cell transfer. This NK burst subsides at days 5–7, when adaptive T and B cell responses lead to viral clearance and tumor eradication during successful immune responses. In this review, we want to shed light on this innate and early NK activation. Specifically, we want to address the questions of where NK cells are recruited from, which interactions lead to NK activation, and where this activation takes place. Furthermore, we want to address what role this early NK burst plays during the establishment of immunity and how innate NK activation could be used for immunotherapy.