Model organisms are important in many areas of chemical biology. In metabolomics, model organisms can provide excellent samples for methods development as well as the foundation of comparative phylometabolomics, which will become possible as metabolomics applications expand. Comparative studies of conserved and unique metabolic pathways will help in the annotation of metabolites as well as provide important new targets of investigation in biology and biomedicine. However, most chemical biologists are not familiar with genetics, which needs to be considered when choosing a model organism. In this review we summarize the strengths and weaknesses of several genetic systems, including natural isolates, recombinant inbred lines, and genetic mutations. We also discuss methods to detect targets of selection on the metabolome.