Brain lesions, such as the ones caused by stroke or tumors, disrupt normal brain function and cause a wide spectrum of neurological and psychiatric symptoms. Studying brain lesions has formed the foundation for localization of symptoms throughout the history of neurology, providing unique causal evidence. In exceedingly rare cases, spontaneous brain lesions can improve pre-existing symptoms, which is referred to as paradoxical functional facilitation. Iatrogenic brain lesions can provide similar functional benefit. Both types of lesions have helped lead to identification of deep brain stimulation targets. However, paradoxical functional facilitation is rare and lesions improving similar symptoms can occur in multiple different neuroanatomical locations, leaving the optimal treatment target unclear. Emerging new techniques combining causal and beneficial brain lesions with the human connectome have opened the door for systematic search of new and improved therapeutic targets for functional neurosurgery.