Genetic association studies have traditionally focused on associations between individual single nucleotide polymorphisms (SNPs) and disease. Standard analysis ignores interactions between multiple SNPs and environmental exposures explaining a small portion of disease heritability: the often-cited issue of “missing heritability.” We present a novel three-step analytic framework for modeling gene-environment interactions (GEIs) between an angiogenesis candidate-gene pathway and three lifestyle exposures (dietary protein, smoking, and alcohol consumption) on colon cancer risk and survival. Logic regression was used to summarize the gene-pathway effects, and GEIs were modeled using logistic regression and Cox proportional hazards models. We analyzed data from 1541 colon cancer case patients and 1934 control subjects in the Diet, Activity and Lifestyle as a Risk Factor for Colon Cancer Study. We identified five statistically significant GEIs for colon cancer risk. For risk interaction, odds ratios (ORINT) and 95% confidence intervals (CIs) were FLT1(rs678714) and BMP4(rs17563) and smoking (ORINT = 1.64, 95% CI = 1.11 to 2.41 and ORINT = 1.60, 95% CI = 1.10 to 2.32, respectively); FLT1(rs2387632 OR rs9513070) and protein intake (ORINT = 1.69, 95% CI = 1.03 to 2.77); KDR(rs6838752) and TLR2(rs3804099) and alcohol (ORINT = 1.53, 95% CI = 1.10 to 2.13 and ORINT = 1.59, 95% CI = 1.05 to 2.38, respectively). Three GEIs between TNF, BMP1, and BMPR2 genes and the three exposures were statistically significant at the 5% level in relation to colon cancer survival but not after multiple-testing adjustment. Adopting a comprehensive biologically informed candidate-pathway approach identified GEI effects on colon cancer. Findings may have important implications for public health and personalized medicine targeting prevention and therapeutic strategies. Findings from this study need to be validated in other studies.