In organisms from Drosophila to mammals, the musculature is comprised of an elaborate array of distinct fibers that are generated by the fusion of committed myoblasts. These muscle fibers differ from each other in features that include location, pattern of innervation, site of attachment, and size. The sizes of the newly formed muscles of an embryo are controlled in large part by the number of cells that form the syncitial fiber. Over the past few decades, an extensive body of literature has described the process of myoblast fusion in vertebrates, relying primarily on the strengths of tissue culture model systems. More recently, genetic studies in Drosophila embryos have provided new insights into the process. Together, these studies define the steps necessary for myoblast differentiation, the acquisition of fusion competence, the recognition and adhesion between myoblasts, and the fusion of two lipid bilayers into one. In this review, we have attempted to combine insights from both Drosophila and vertebrate studies to trace the processes and molecules involved in myoblast fusion. Implicit in this approach is the assumption that fundamental aspects of myoblast fusion will be similar, independent of the organism in which it is occurring.