Physical forces direct cell behaviors such as differentiation, migration, and division. Cell fusion is no exception. In addition to protein-based machinery, mechanical stresses, pressure differentials, and electric fields have been suggested to also regulate fusion. Decades of research have identified numerous fusogenic membrane proteins, yet the precise mechanisms of their action remain unclear. Here, we outline a biophysical framework that links the physics of model membranes to fusion in living cells. We describe how surface free energy, membrane curvature, tension, pressure, and electric fields can play a role in driving fusion, drawing on insights from both model membranes and cellular systems. Finally, we highlight how these biophysical factors contribute to fusion in the context of placental development and how they may inform future work in skeletal muscle, bone tissue, and tumors. By integrating molecular and biophysical perspectives, we provide a starting point to uncover conserved principles of cell fusion and advance a more integrated view of fusion as both a biochemical and biophysical process.