Ehlers-Danlos syndrome (EDS) is a heterogeneous heritable connective tissue disorder characterized by hyper-extensible skin, hypermobile joints and fragile vessels. The molecular causes of this disorder are often, although not strictly, related to collagens and to the enzymes that process these proteins. The classical form of the syndrome, which will be principally discussed in this review, can be due to mutations on collagen V, a fibrillar collagen present in small amounts in affected tissues. However, collagen I and tenascin have also been demonstrated to be involved in the same type of EDS. Moreover gene disruption of several other matrix molecules (thrombospondin, SPARC, small leucine rich proteoglycans...) in mice, lead to phenotypes that mimic EDS and these molecules have thus emerged as new players. As collagen V remains the prime candidate, we discuss, based on fundamental and clinical observations, its physiological role. We also explore its potential interactions with other matrix molecules to determine tissue properties.