Hyaluronan and versican are extracellular matrix (ECM) components that are enriched in the provisional matrices that form during the early stages of development and disease. These two molecules interact to create pericellular “coats” and “open space” that facilitate cell sorting, proliferation, migration, and survival. Such complexes also impact the recruitment of leukocytes during development and in the early stages of disease. Once thought to be inert components of the ECM that help hold cells together, it is now quite clear that they play important roles in controlling cell phenotype, shaping tissue response to injury and maintaining tissue homeostasis. Conversion of hyaluronan-/versican-enriched provisional matrix to collagen-rich matrix is a “hallmark” of tissue fibrosis. Targeting the hyaluronan and versican content of provisional matrices in a variety of diseases including, cardiovascular disease and cancer, is becoming an attractive strategy for intervention. •Versican and hyaluronan are enriched in provisional matrices.•Provisional matrices occur in development and early stages of disease pathogenesis.•Versican/hyaluronan complexes facilitate cell proliferation and migration.•Versican/hyaluronan interacts with immune and inflammatory cells.•Inhibition of versican and/or hyaluronan accumulation alters disease progression.