The goal of case-control association studies is to find genetic variants in the human genome that influence common traits. The Human Genome and HapMap projects have added fresh impetus to this goal by cataloguing the raw genetic data behind human DNA variation. Studies that associate these genetic variants with phenotype improve both molecular diagnostics and drug discovery and offer clinicians important opportunities to improve care of patients. In this review I focus on case-control studies, which are the most widely used design and expected to be the most powerful. I also address the problem of case-control non-replication, which is widespread despite enormous effort and use of resources. Important causes of non-replication include inadequate statistical power to detect small and moderate effects, phenotype heterogeneity, population stratification, publication bias, and multiple comparison testing.