The sphenoid sinus can be approached through the ethmoid, nasal or septal zones of the anterior wall. Case studies, fresh/fixed cadaver material and radiologic examinations, including three-dimensional CT reconstructions, were used to define the anatomic conditions governing the safest penetration of each zone. The ethmoid zone was often associated with anatomic variations such as posterior and superior placement of ethmoid cells which dictated caution. The transnasal route was best used for isolated sphenoid disease since nasal disease caused significant bleeding. A detailed description of the vomer-ethmoid relationship outlines the advantages of using the septal zone. The actual zone used to enter the sphenoid sinus must be determined by the nature of the disease process to be treated and therefore a detailed knowledge of the normal and aberrant anatomy of each zone, as elaborated by the radiological road map, is required to prevent complication.