Surgical treatment of corneal endothelial disease has evolved dramatically. Penetrating keratoplasty (PK) has now been replaced largely by endothelial keratoplasty (EK). For the treatment of endothelial disease, EK yields superior visual results, less topographic change, and improved tectonic strength compared with PK. The tremendous benefit afforded patients by EK has been made accessible through pioneering work by surgeons worldwide and advances in eye bank preparation of tissue. Descemet stripping automated endothelial keratoplasty (DSAEK) remains the predominant EK procedure in use worldwide. However, advances in Descemet membrane endothelial keratoplasty (DMEK) tissue preparation have led to an exponential rise in the number of these surgeries performed in recent years. Recent evidence suggests potential for several new targeted endothelial disease treatment strategies. These include anterior chamber injection of cultured corneal endothelial cells and use of rho kinase (ROCK) inhibitors, which can lead to repopulation and improved function of the endothelial layer in certain situations.