Epidemiologic studies have suggested for decades an association between dietary fat and cancer risk. A large body of work performed in tissue culture and xenograft models of cancer supports an important role of various types of fat in modulating the cancer phenotype. Yet, the molecular mechanisms underlining the effects of fat on cancer initiation and progression are largely unknown. The relationships between saturated fat, polyunsaturated fat, cholesterol or phytanic acid with cancer have been reviewed respectively. However, few have considered the relationship between all of these fats and cancer. The purpose of this review is to present a more cohesive view of dietary fat-gene interactions, and outline a working hypothesis of the intricate connection between fat, genes and cancer.