Thrombospondins (TSPs) are extracellular regulators of cell–matrix interactions and cell phenotype. The most highly conserved region of all TSPs are the calcium‐binding type 3 (T3) repeats and the C‐terminal globular domain (CTD). The crystal structure of a cell‐binding TSP‐1 fragment, spanning three T3 repeats and the CTD, reveals a compact assembly. The T3 repeats lack secondary structure and are organised around a core of calcium ions; two DxDxDGxxDxxD motifs per repeat each encapsulate two calcium ions in a novel arrangement. The CTD forms a lectin‐like β‐sandwich and contains four strictly conserved calcium‐binding sites. Disruption of the hairpin structure of T3 repeats 6 and 7 decreases protein secretion and stability. The availability for cell attachment of an RGD motif in T3 repeat 7 is modulated by calcium loading. The central architectural role of calcium explains how it is critical for the functions of the TSP C‐terminal region. Mutations in the T3 repeats of TSP‐5/COMP, which cause two human skeletal disorders, are predicted to disrupt the tertiary structure of the T3–CTD assembly.