Although plamsa proteins play important roles in biological processes and are the direct targets of many drugs, there is limited knowledge of the genetic factors determining inter-individual variation in plasma protein levels. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a 4-fold increase on existing knowledge, including trans associations for 1,104 proteins. To understand consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show overlap of pQTL with eQTL, as well as with disease-associated loci, and show support for causal roles for protein biomarkers in disease using Mendelian randomisation analysis. By linking genetic factors to disease via specific proteins, our analyses suggests potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.