Corpus callosotomy (CC) has a long history for the treatment of drug-resistant epilepsy. With the emergence of alternative treatment modalities, such as vagal nerve stimulation and thalamic neuromodulation, on one hand and diverging techniques for callosotomy (including microsurgery, endoscope-assisted surgery, laser interstitial thermal therapy, and radiosurgery) on the other, the role of corpus callosotomy can be reappraised. We review the history and neuroscientific basis of corpus callosotomy, which have yielded new insights into the required extent of disconnection. We then survey novel techniques and review efficacy data comparing these various forms of callosotomy and alternative treatments. The evolution of corpus callosotomy opens the opportunity to tailor the surgical treatment of epilepsy to a patient’s unique disease, anatomy, and circumstance.