Apolipoprotein E (ApoE) alleles have been reported to affect the clinical outcome of numerous cardiovascular, neurodegenerative, and viral infectious diseases, including atherosclerosis, Alzheimer's disease (AD), hepatitis C, and HIV. The major alleles of ApoE are 2, 3, and 4. ApoE genotypes have been hypothesized to regulate many biological functions, resulting in significant changes in the onset and/or outcome (severity and duration) of several clinical conditions. Based on genetic analyses in human and animal studies using knockout (ApoE -/-) mice and mice transgenic for human 3 and 4, we present evidence that strongly suggests that the ApoE alleles can regulate the pathogenesis of ocular herpes simplex virus type 1 (HSV-1) infections. This review will summarize the major studies that support this hypothesis. Significant gender based differences in HSV-1 pathogenesis have also been reported, suggesting that hormonal regulation combined with ApoE genotype plays a significant role in HSV-1 pathogenesis. Identification of specific mechanisms in ocular HSV-1 infections related to the ApoE alleles and gender could lead to therapeutic intervention based on the properties of the apoE isoforms. While many clinical investigations have been reported and, to a lesser extent, transgenic mouse studies have been conducted, no specific mechanisms of how ApoE induces or alters clinical disease are known.