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Background Natural variation offers a powerful approach for assigning function to DNA sequence—a pressing challenge in the age of high throughput sequencing technologies. Scope of Review Here we review comparative genomic approaches that are bridging the sequence–function and genotype–phenotype gaps. Reverse genomic approaches aim to analyse sequence to assign function, whereas forward genomic approaches start from a phenotype and aim to identify the underlying genotype responsible. Major Conclusions Comparative genomic approaches, pioneered in budding yeasts, have resulted in dramatic improvements in our understanding of the function of both genes and regulatory sequences. Analogous studies in other systems, including humans, demonstrate the ubiquity of comparative genomic approaches. Recently, forward genomic approaches, exploiting natural variation within yeast populations, have started to offer powerful insights into how genotype influences phenotype and even the ability to predict phenotypes. General Significance Comparative genomic experiments are defining the fundamental rules that govern complex traits in natural populations from yeast to humans. This article is part of a Special Issue entitled Systems Biology of Microorganisms., Research Highlights ► A major challenge in biology is the assigning of function to DNA sequence. ► We review the power of comparative genomics and natural variation. ► We contrast forward and reverse genomic approaches. ► We present a case study of telomere biology as a complex phenotype.