The molecular analysis of limb bud development in vertebrates continues to fuel our understanding of the gene regulatory networks that orchestrate the patterning, proliferation and differentiation of embryonic progenitor cells. In recent years, systems biology approaches have moved our understanding of the molecular control of limb organogenesis to the next level by incorporating next generation ‘omics’ approaches, analyses of chromatin architecture, enhancer-promoter interactions and gene network simulations based on quantitative datasets into experimental analyses. This Review focuses on the insights these studies have given into the gene regulatory networks that govern limb development and into the fin-to-limb transition and digit reductions that occurred during the evolutionary diversification of tetrapod limbs.