The enormous chemical diversity and the broad range of biological activities of secondary metabolites raise many questions about their role in nature and the specific traits leading to their evolution. The answers to these questions will not only be of fundamental interest but may also provide lessons that could help to improve the screening protocols of pharmaceutical companies and strategies for rational secondary metabolite engineering. In this review, we try to dissect evolutionary principles leading to the emergence, distribution, diversification and selection of genes involved in secondary metabolite biosyntheses. We give an overview about recent insights into the evolution of the different types of polyketide synthases (PKS) in microorganisms and plants and highlight unique mechanisms underlying polyketide diversity. Although phylogenetic and experimental data have significantly increased our knowledge about the role and evolution of secondary metabolites in the last decades there is still much dissent about the impact of natural selection. In order to understand the evolution towards metabolic diversity we therefore need more thorough investigations of the ecological role of secondary metabolites in the future.