Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy in humans (Ojemann, 1997; Engel, 2001). However, TLE is often difficult to control with antiepileptic drugs and as a result, about 50% of TLE patients (Ojemann, 1997) require other treatments. Often, surgical removal of the epileptogenic parts of the medial temporal lobe (MTL) is an option. After surgical treatment, 70%–90% of patients become free of disabling seizures (Engel, 2001). However, planning for such resective surgery requires extensive preparation to evaluate the location and extent of the resection as well as an evaluation of possible loss of function resulting from the resection. Accurate localization can be challenging and time consuming. This is particularly true for hippocampal sclerosis, which is one of the most common pathologies that results in TLE. The neuronal loss in the hippocampus is often hard to detect using conventional structural MRI, and noninvasive techniques, chiefly electroencephalography (EEG) and magnetoencephalography, have limited ability to monitor hippocampal activity. If noninvasive methods fail to clearly localize the seizure onset zone, invasive recording techniques are necessary (Spencer et al., 2007). These include subdural grids of electrodes placed on the surface of the cortex as well as depth electrodes, which are implanted semichronically for up to several weeks for seizure monitoring. Depth electrodes are implanted to record intracranial EEG signals directly from areas suspected to generate seizures, such as the hippocampus. Apart from their clinical utility, depth electrodes provide a rare and unique opportunity to study the human brain. These clinical situations provide one of the very few possibilities to record invasively from the human brain with techniques, otherwise only feasible with animal models. In this chapter, we provide an overview of the techniques by which such recordings can be performed to study single-neuron activity in awake humans for research purposes.