The extracellular matrix (ECM) is an organised mesh of secreted proteins that provides structure, organisation and orientation to tissues and influences a spectrum of cell behaviours of direct relevance to disease and drug discovery. Many drugs currently in development target components of the ECM, yet most drug discovery teams perceive the ECM as a barrier to efficacious drug action, rather than a therapeutic target. Here we review current therapeutic approaches and consider potentially novel druggable opportunities to target the ECM, taking into account the factors that make it both unique and challenging, including its evolutionary history and innate multi-dimensional complexity.