Neuroimaging studies have shown that spontaneous brain activity is characterized as changing networks of coherent activity across multiple brain areas. However, the directionality of functional interactions between the most active regions in our brain at rest remains poorly understood. Here, we examined, at the whole-brain scale, the main drivers and directionality of interactions that underlie spontaneous human brain activity by applying directed functional connectivity analysis to electroencephalography (EEG) source signals. We found that the main drivers of electrophysiological activity were the posterior cingulate cortex (PCC), the medial temporal lobes (MTL), and the anterior cingulate cortex (ACC). Among those regions, the PCC was the strongest driver and had both the highest integration and segregation importance, followed by the MTL regions. The driving role of the PCC and MTL resulted in an effective directed interaction directed from posterior toward anterior brain regions. Our results strongly suggest that the PCC and MTL structures are the main drivers of electrophysiological spontaneous activity throughout the brain and suggest that EEG-based directed functional connectivity analysis is a promising tool to better understand the dynamics of spontaneous brain activity in healthy subjects and in various brain disorders.