Endothelin-1 (ET-1) and adrenomedullin (ADM) are circulating vasoactive peptides involved in vascular homeostasis and endothelial function. Elevated levels of plasma ET-1 and ADM, and their biologically stable surrogates, C-terminal-pro-endothelin-1 (CT-pro-ET-1) and midregional proadrenomedullin (MR-pro-ADM), are predictors of cardiac death and heart failure. We studied the association of common genetic variation with MR-pro-ADM and CT-pro-ET-1 by genome-wide association analyses in 3444 participants of European ancestry. We performed follow-up genotyping of single nucleotide polymorphisms (SNPs) that showed suggestive or significant association in the discovery stage in additional 3230 participants. The minor variants in KLKB1 (rs4253238) and F12 (rs2731672), both part of the kallikrein-kinin system, were associated with higher MR-pro-ADM (P=4.46E-52 and P=5.90E-24, respectively) and higher CT-pro-ET-1 levels (P=1.23E-122 and P=1.26E-67, respectively). Epistasis analyses showed a significant interaction between the sentinel SNP of F12 and KLKB1 for both traits. In addition, a variant near the ADM gene (rs2957692) was associated with MR-pro-ADM (P=1.05E-12) and a variant in EDN-1 (rs5370) was associated with CT-pro-ET-1 (P=1.49E-27). The total phenotypic variation explained by the genetic variants was 7.2% for MR-pro-ADM and 14.6% for CT-pro-ET-1. KLKB1 encodes plasma kallikrein, a proteolytic enzyme known to cleave high-molecular-weight kininogen to bradykinin and prorenin to renin. We cloned the precursors of ADM and ET-1 and demonstrated that purified plasma kallikrein can cleave these recombinant proteins into multiple smaller peptides. The discovery of genetic variants in the kallikrein-kinin system and in the genes encoding pre-pro-ET-1 and pre-pro-ADM provides novel insights into the (co-)regulation of these vasoactive peptides in the vascular system.