This year marks the 40th anniversary of the discovery by Ed Lewis of the property of collinearity in the bithorax gene complex in Drosophila. This landmark work illustrated the need to understand regulatory mechanisms that coordinate expression of homeotic gene clusters. Through the efforts of many groups, investigation of the Hox gene family has generated many fundamental findings on the roles and regulation of this conserved gene family in development, disease and evolution. This has led to a number of important conceptual advances in gene regulation and evolutionary biology. This article presents some of the history and advances made through studies on Hox gene clusters.