The Chen lab studies mechanisms underlying cell-cell fusion, a fundamental cellular process in the conception, development and physiology of multicellular organisms. We approach this question using a multifaceted approach including genetics, molecular biology, biochemistry, biophysics, live imaging, super-resolution microscopy and electron microscopy. Starting with a forward genetic screen in Drosophila, we have identified multiple evolutionarily conserved core components of the myoblast fusion signaling cascade, and, more importantly, discovered a novel cellular mechanism underlying myoblast fusion. We show that myoblast fusion is an asymmetric process in which one cell invades its fusion partner using actin-propelled membrane protrusions to promote fusion pore formation. Building on insights we learned from myoblast fusion in vivo, we have reconstituted high-efficiency cell-cell fusion in an otherwise non-fusogenic, non-muscle cell line and uncovered a previously unrecognized function for the actin-propelled membrane protrusions in fusogen engagement. Similar actin-based membrane protrusions have since been observed in the fusion of mammalian muscle and non-muscle cells, suggesting that invasive membrane protrusions are used as a conserved and universal mechanism to promote cell-cell fusion. Furthermore, we have discovered a mechanosensory response in the receiving fusion partner and demonstrated that mechanical tension is a driving force for cell-cell fusion. Our work to date has established a biophysical framework for understanding cell-cell fusion – the interplay between the pushing forces and the resisting forces from the two fusion partners at the fusogenic synapse brings the apposing cell membranes into close proximity to facilitate fusogen engagement and membrane fusion. This new conceptual framework has fundamentally changed our understanding of cell-cell fusion and has become a widely accepted paradigm in the field. Current work in the Chen lab aims to address major unanswered questions in cell-cell fusion, including the identification of the elusive myoblast fusogen and investigating the function of lipids and curvature-binding proteins in cell-cell fusion. We are also interested in understanding how mechanical stimuli are transduced from cell membrane to the actomyosin network and how cell-cell fusion is regulated in vertebrate muscle development and regeneration.