Functional neuroimaging with positron emission tomography (PET) is one of the cornerstones for studying the central nervous system effects of general anesthetics and anesthesia mechanisms. General anesthesia offers a unique and safe way to directly manipulate consciousness, and can thus be used as a powerful research tool to study the neurobiology of human consciousness. In this chapter, we will address the possibilities of PET imaging in revealing the mysteries of general anesthesia and anesthetic induced unconsciousness and summarize some of the recent advancements in the field. Importantly, we will discuss possible ways to separate brain activity changes associated with the changing level of consciousness from the concentration or dose-dependent direct or indirect drug effects on the brain. We will try to demonstrate how state-of-the-art clinical pharmacology, use of specific anesthetic drugs, and innovative study design solutions could be utilized.