Carcinogenesis – the process of cancer formation – is commonly discussed in terms of genetic alterations that lead to deregulation of cell growth. Recently, there has been a resurgence of interest in epigenetic factors and, in particular, the role of the stromal microenvironment and angiogenesis in tumor formation. In this article, cancer is presented as a disease of the developmental processes that govern how cells organize into tissues and tissues into organs. This histogenetic perspective raises the possibility that epithelial–mesenchymal interactions and the extracellular matrix (basement membrane) that is deposited through these interactions may actively contribute to the carcinogenic process. Experimental work is reviewed that confirms that extracellular matrix plays a key role in normal histodifferentiation during both epitheliogenesis and angiogenesis, and that epigenetic deregulation of cell–matrix interactions may actively promote tumor initiation and progression. The contributions of integrins, cytoskeleton, tensegrity and local variations in extracellular matrix mechanics to these processes are discussed, as are the implications of this work for future studies on cancer formation.