AbstractDecellularization removes cellular antigens while preserving the ultrastructure and composition of extracellular matrix (ECM). Decellularized ECM (DECM) scaffolds have been widely used in various tissue engineering applications with varying levels of success. The mechanical, architectural and bioactive properties of a DECM scaffold depend largely on the method of decellularization and dictate its clinical efficacy. This article highlights the advantages and challenges associated with the clinical use of DECM scaffolds. Poor mechanical strength is a significant disadvantage of some DECM scaffolds in the repair of load-bearing tissues as well as critical-size defects, where long-term mechanical support is required for the regenerating tissue. Combining DECM scaffolds with synthetic biocompatible polymers could provide a useful strategy to circumvent the issues of poor mechanical stability. This article reviews studies that have combined DECM scaffolds from various tissues with synthetic polymers to create hybrid scaffolds using electrospinning. These hybrid scaffolds provide a mechanical backbone while retaining the bioactive properties of DECM, thus offering a significant advantage for tissue engineering and regenerative medicine applications.