Candidate polymorphism-based genetic epidemiological studies have yielded little success in the search for low-penetrance breast cancer susceptibility genes. The lack of progress is partially due to insufficient coverage of genomic regions with genetic markers, as well as economic constraints, limiting both the number of genetic targets and the number of individuals being studied. Recent rapid advances in high-throughput genotyping technology and our understanding of genetic variation patterns across the human genome are now revolutionizing the way in which genetic epidemiological studies are being designed and conducted. Genetic epidemiological studies are quickly progressing from candidate gene studies to comprehensive pathway investigation and, further, to genomic epidemiological studies where the whole human genome is being interrogated to identify susceptibility alleles. This paper reviews the evolving approaches in the search for low-penetrance breast cancer susceptibility gene variants and discusses their potential promises and pitfalls.