Genome-wide association studies of complex traits have mapped >15,000 common single nucleotide variants (SNVs). Likewise, applications of massively parallel nucleic acid sequencing technologies often referred to as next-generation sequencing to molecular genetic studies of complex traits have catalogued a large number of rare variants (population frequency of <0.01) in cases with complex traits. Moreover, high-throughput nucleic acid sequencing, variant burden analysis, and linkage studies are illuminating the presence of large number of SNVs in cases and families with single-gene disorders. The plethora of the genetic variants has exposed the formidable challenge of identifying the causal and pathogenic variants from the enormous number of innocuous common and rare variants that exist in the population and in an individual genome. The arduous task of identifying the causal and pathogenic variants is further compounded by the pleiotropic effects of the variants, complexity of cis and trans interactions in the genome, variability in phenotypic expression of the disease, as well as phenotypic plasticity, and the multifarious determinants of the phenotype. Population genetic studies offer the initial roadmaps and have the potential to elucidate novel pathways involved in the pathogenesis of the disease. However, the genome of an individual is unique, rendering unambiguous identification of the causal or pathogenic variant in a single individual exceedingly challenging. Yet, the focus of the practice of medicine is on the individual, as Sir William Osler elegantly expressed in his insightful quotation: “The good physician treats the disease; the great physician treats the patient who has the disease.” The daunting task facing physicians, patients, and researchers alike is to apply the modern genetic discoveries to care of the individual with or at risk of the disease.