We have been studying the core mechanisms that govern differentiation and tissue-specific gene expression of epithelia. They comprise those dictated by the epithelial-mesenchymal cell-cell relationships and those defined by stem cell and maturational lineage biology. The epithelial-mesenchymal cell-cell relationships are driven by synergistic effects of soluble signals (autocrine, paracrine, endocrine) with the effects of the extracellular matrix, an insoluble complex of collagens, adhesion molecules, proteoglycans and factors bound to these matrix components. Tissue-specific gene expression is mediated by matrix-hormone/growth factor synergistic effect. Most of these influence posttranscriptional regulatory mechanisms (translation, mRNA stability, protein stability, etc.). Transcriptional regulation is governed primarily by soluble signals in combination with proteoglycans and more specifically with those soluble signals in combination with defined epitopes of the proteoglycan’s glycosaminoglycan (GAG) chains. The most potent of these GAG chains are forms of heparins with specific sulfation patterns.