Hypertriglyceridemia is a common complex metabolic trait that is associated with increased atherosclerosis risk, presence of the metabolic syndrome and, with extreme elevation, increased risk of pancreatitis. Hierarchical cluster analysis using clinical and biochemical features of the Frederickson hyperlipoproteinemia types can generate hypotheses for molecular genetic studies. High throughput resequencing of individuals at the extremes of plasma triglyceride concentration has shown that both rare genetic variants with large effects and common genetic variants with moderate effects explain a relatively large proportion of variation. Very recent progress using high-density sets of genome-wide markers have identified additional genetic determinants of plasma triglyceride concentrations, albeit within largely normolipidemic subjects and with small effect sizes. Phenomic evaluation of patients with hypertriglyceridemia might help to clarify genotype–phenotype correlations and responses to interventions.