Abstract Purpose: VEGF receptor 2 (VEGFR-2) plays a crucial role in mediating angiogenic endothelial cell responses via the VEGF pathway, and angiogenesis inhibitors targeting VEGFR-2 are in clinical use. As angiogenesis is a host-driven process, functional heritable variation in KDR, the gene encoding VEGFR-2, may affect VEGFR-2 function and, ultimately, the extent of tumor angiogenesis. Experimental Design: We resequenced KDR using 24 DNAs each from healthy Caucasian, African American, and Asian groups. Nonsynonymous genetic variants were assessed for function by phosphorylation assays. Luciferase reporter gene assays were used to examine effects of variants on gene expression. KDR mRNA and protein expression and microvessel density (MVD) were measured in non–small cell lung cancer (NSCLC) tumor samples, and matching patient DNA samples were genotyped to test for associations with variants of interest. Results: KDR resequencing led to the discovery of 120 genetic variants, of which 25 had not been previously reported. Q472H had increased VEGFR-2 protein phosphorylation and associated with increased MVD in NSCLC tumor samples. −2854C and −2455A increased luciferase expression and associated with higher KDR mRNA levels in NSCLC samples. −271A reduced luciferase expression and associated with lower VEGFR-2 levels in NSCLC samples. −906C and 23408G associated with higher KDR mRNA levels in NSCLC samples. Conclusions: This study has defined KDR genetic variation in 3 populations and identified common variants that impact on tumoral KDR expression and vascularization. These findings may have important implications for understanding the molecular basis of genetic associations between KDR variation and clinical phenotypes related to VEGFR-2 function. Clin Cancer Res; 17(16); 5257–67. ©2011 AACR.