Genotype-phenotype studies in pharmacogenomics promise to identify the genetic factors that contribute substantially to variation in individual drug response. While most genetic association studies have failed to deliver this promise, several recent examples serve as a reminder that these associations do exist and can be identified when investigated using well-designed studies. Here, we describe the path taken to identify the association between common vitamin K epoxide reductase complex subunit 1 genetic variation and warfarin dosing in patients. We also describe the key elements that led the way, such as definition of the phenotype, confirmation of a genetic component, determination of biological plausibility and selection of genetic polymorphisms. We also describe several avenues that are yet to be explored for the specific vitamin K epoxide reductase complex subunit 1 warfarin example that can also be generalized as future directions for many genetic association studies in pharmacogenomics. These future avenues will be best explored using diverse approaches encompassing clinical, statistical and genomic methods currently being developed for genotype-phenotype studies in human populations.