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Fibrillar collagens are the most abundant proteins in the extracellular matrix. Not only do they provide structural integrity to all of the connective tissues in the human body, but also their interactions with multiple cell receptors and other matrix molecules are essential to cell functions, such as growth, repair, and cell adhesion. Although specific binding sequences of several receptors have been determined along the collagen monomer, processes by which collagen binding partners recognize their binding sites in the collagen fibril, and the critical driving interactions, are poorly understood. The complex molecular assembly of bundled triple helices within the collagen fibril makes essential ligand binding sites cryptic or hidden from the molecular surface. Yet, critical biological processes that require collagen ligands to have access to interaction sites still occur. In this contribution, we will discuss the molecular packing of the collagen I fibril from the perspective of how collagen ligands access their known binding regions within the fibril, and we will present our analysis of binding site accessibility from the fibril surface. Understanding the basis of these interactions at the atomic level sets the stage for developing drug targets against debilitating collagen diseases and using collagen as drug delivery systems and new biomaterials.