The morphogenesis of the vascular system is a complex and interesting example of cellular self-organization, but understanding the principles of the process remains an outstanding challenge in the field of developmental biology. The two key sequential processes that underlie the vascular developmental process include vasculogenesis and angiogenesis. Vasculogenesis is the process by which endothelial progenitor cells interact to form a honeycomb-like network of channels of uniform diameter called the primary vascular plexus. Angiogenesis is the growth and remodeling of this structure to form new vessels after the onset of flow and is a process known to be critical during wound healing, development, and cancer. Here, we describe our work developing and characterizing native type I collagen matrices for three-dimensional cell culture and then using these matrices with human umbilical vein endothelial cells to study the critical steps and mechanisms of cellular selforganization during vascular network formation in vitro. Because the primary vascular plexus precedes the functional vascular network in vivo, it is an appropriate base state for investigating angiogenesis and the formation of the mature vascular system. An accurate understanding of this process would advance research in basic cell biology and angiogenesis during development and disease and form the basis of powerful tissue engineering strategies.