Introduction The purpose of this study was to define the anatomical relationships of the pterygopalatine fossa (PPF) and its operative implications in skull base surgical approaches. Methods Ten cadaveric heads were dissected at the Dianne and M Gazi Yasargil Educational Center MicrosurgicaLaboratory, in Little Rock, AK, USA. The PPF was exposed through an extended dissection with mandible and pterygoid plate removal. Results The PPF has the shape of an inverted cone. Its boundaries are the pterygomaxillary fissure; themaxilla, anteriorly; themedial plate of the pterygoid process, and greater wing of the sphenoid process, posteriorly; the palatine bone,medially; and the body of the sphenoid process, superiorly. Its contents are the maxillary division of the trigeminal nerve and its branches; the pterygopalatine ganglion; the pterygopalatine portion of the maxillary artery (MA) and its branches; and the venous network. Differential diagnosis of PPF masses includes perineural tumoral extension along the maxillary nerve, schwannomas, neurofibromas, angiofibromas, hemangiomas, and ectopic salivary gland tissue. Transmaxillary and transpalatal approaches require extensive resection of bony structures and are narrow in the deeper part of the approach, impairing the surgical vision and maneuverability. Endoscopic surgery solves this problem, bringing the light source to the center of the surgical field, allowing proper visualization of the surgical field, extreme close-ups, and different view angles. Conclusion We provide detailed information on the fossa’s boundaries, intercommunications with adjacent structures, anatomy of the maxillary artery, and its variations. It is discussed in the context of clinical affections and surgical approaches of this specific region, including pterygomaxillary disjunction and skull base tumors.