Single neuronal studies remain the gold standard for studying brain function. Here, we describe a protocol for studying task-related single neuronal activity in human subjects during neurosurgical procedures involving microelectrode recordings. This protocol has two phases: a pre-operative and intra-operative phase. During the pre-operative phase we discuss informed consent, equipment setup, and behavioral testing. During the intra-operative phase we discuss the procedure for microelectrode recordings. Because patients are often awake during these procedures, this protocol can be performed in conjunction with behavioral tasks to study a variety of cognitive functions. We describe the protocol in detail and provide two examples of expected results. Additionally, we discuss potential difficulties and pitfalls related to intra-operative studies. This protocol takes approximately 1.5 hours to complete.