The Ehlers-Danlos Syndromes comprise a heterogeneous group of heritable connective tissue disorders, in which patients share the presence of joint hypermobility, skin hyperextensibility and soft tissue fragility. The consequences of this tissue fragility are associated with important morbidity and increased mortality. In addition, many patients suffer from chronic intractable pain with a severe impact on quality of life. For many EDS types, molecular defects have been identified that disturb the primary structure, biosynthesis and/or supramolecular organization of fibrillar collagens, ultimately leading to a disorganized extracellular matrix (ECM). Yet, for a substantial proportion of EDS patients, the underlying genetic defect remains unsolved. Furthermore, the biological processes that lead to various phenotypic outcomes in EDS are poorly understood. As such, there are still major gaps in the diagnosis and management of EDS. Combining deep phenotyping tools with state-of-the-art and innovative molecular, biochemical and imaging techniques, both in clinic, in murine and in zebrafish models for EDS, I aim to uncover molecular mechanisms which will inform diagnostic assays, biomarkers and/or treatment targets. To increase our understanding of mechanisms that drive and maintain EDS-related pain, I will also assess pain behavior and study the link between an aberrant ECM and structural and functional changes in the nervous tissue in these models.