Keratinocyte carcinomas (KC) which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin represent the most common malignancies in the world. UVR is the major risk factor associated with KC, and contributes to skin cancer carcinogenesis both as a mutagen and an immune suppressing agent. Exposures to arsenic, immunosupressive medications, beta-HPV, and individual susceptibility risk factors including genetic variability have also been implicated in KC development. Previous research was largely focused on the role of adaptive immunity in KC, while the role of innate immunity has not been fully investigated. Recent studies, including those on the action of Imiquimod, point to the centrality of innate immunity in KC pathogenesis. Natural killer (NK) cells of the innate immune system are the first line of defense against transformed and infected cells. NK cell killing capacity is determined by multiple inhibitory and activating cell surface receptors, including broad cellular-stress sensing natural killer group 2 member D (NKG2D) receptors, and highly diverse in gene content, copy number, and allelic polymorphisms killer-cell immunoglobulin-like receptors (KIR) that recognize self-human leukocyte antigen class I (HLA-I) ligands. Inter-individual variability of the KIR locus, and its interaction with cognate HLA-I, has been increasingly implicated in various disease settings including cancer. Genetic variability of NKG2D receptor activity has also been described in epithelial cancers. Given that NK cell function is influenced by these two classes of receptors, we hypothesized that genetic variability at these loci impacts innate immunity and BCC and SCC risk. Using a large population-based case-control study, a three part investigation was conducted. First investigation examined whether two genetic variants related to high natural cytotoxic activity of the NKG2D receptor decrease risk of KC and are modified by susceptibility and exposure factors including: sex, skin type, number of severe sunburns, glucocorticoids, and arsenic. This revealed differential effects of NKG2D genotype on KC risk by sex and skin type. The second study, determined whether KIR gene content alone and in combination with HLA-I ligands was associated with KC risk. The results suggested interactions of the activating KIR and HLA-I ligands may be implicated in control of BCC and to a lesser degree of SCC. The third study investigated the combined effects of KIR and NKG2D. NKG2D activity was assigned based on the number of alleles with high cytotoxic activity, and activating KIR were grouped based on the presence of 2DS1, 3DS1 and 2DS5 that were previously associated with reduced KC risk. The results showed reduced KC risk with the highest activating profile (containing 3 activating KIR and 2 or more NKG2D high activity alleles). Taken together, the results suggest a greater involvement of the innate immune response in the etiology of BCC, and to a lesser extent of SCC. In the context of SCC, these data suggest increased inflammation may deregulate the innate immune response.