Extensive morphological variation found in mammals reflects the wide spectrum of their ecological adaptations. The highest morphological diversity is present in the craniofacial region, where geometry is mainly dictated by the bony skull. Mammalian craniofacial development represents complex multistep processes governed by numerous conserved genes that require precise spatio-temporal control. A central question in contemporary evolutionary biology is how a defined set of conserved genes can orchestrate formation of fundamentally different structures, and therefore how morphological variability arises. In principle, differential gene expression patterns during development are the source of morphological variation. With the emergence of multicellular organisms, precise regulation of gene expression in time and space is attributed tocis-regulatory elements. These elements contribute to higher-order chromatin structure and together withtrans-acting factors control transcriptional landscapes that underlie intricate morphogenetic processes. Consequently, divergence incis-regulation is believed to rewire existing gene regulatory networks and form the core of morphological evolution. This review outlines the fundamental principles of the genetic code and genomic regulation interplay during development. Recent work that deepened our comprehension ofcis-regulatory element origin, divergence and function is presented here to illustrate the state-of-the-art research that uncovered the principles of morphological novelty.This article is part of the theme issue ‘The mammalian skull: development, structure and function’.