Multifactorial diseases are caused by multiple genetic and environmental factors. The study of multifactorial disease involves several steps, including determination of disease heritability, segregation analysis to determine the genetic model, linkage or association mapping to identify genetic loci underlying the disease, fine mapping to determine the causal variants, and replication and functional analysis to confirm the initial findings. The HapMap and 1000 Genomes projects, which surveyed genetic variation in a diverse set of human populations, led to advances in affordable high-throughput genotyping technology that enabled myriad genome-wide association studies for many common diseases. Direct sequencing, which allows for unbiased assessment of all sources of genetic variation, has been used more recently. Important statistical considerations include adjusting for population admixture to prevent false positive associations, quality control, appropriate design and analysis of discovery and validation sets, and adjustment for multiple testing. The power and interpretability of genetic studies are improved by incorporating prior biological knowledge such as genes or pathways, and by performing cross-platform integration and functional assessment. Many changes and advances have occurred in the study of multifactorial diseases with advances in genotyping technology, and yet more change is likely in the years to come.