At any given time, a natural killer cell must commit to life or death. How does a natural killer cell decide on this demanding task? Of course, this life-threatening decision is primarily orchestrated at the cell surface by protein-protein interactions. Thus, natural killer cells are equipped with an array of receptors that are responsible for sending signals in order to activate or inhibit their cytolytic activity. The goal of this review is to provide a functional and structural overview on innate immunity cell surface receptors in humans, which emerging data implicate to play a relevant role in different diseases. Although extremely interesting, it must be considered that this issue is mainly based on genetic correlation and there are controversial published data that will need further study.