A significant diversity of tissue types interface at the base of the skull and contribute to the diagnostic challenges of skull base surgical pathology. Advances in surgical technique now permit biopsy and resection of lesions previously termed “inoperable.” Retrospective review was made of all pathology specimens from skull base surgeries performed at the University of California Davis Medical Center from 1990 to 1996. Surgical biopsies and resections were performed on 186 patients who had 33 distinctive diagnoses. Any preoperative biopsy or tissue from referring institutions was reviewed prior to skull base surgery. One hundred eighteen patients had benign lesions, the most frequent of which were pituitary adenoma (55) and acoustic neuroma (27). Other benign lesions included angiofibroma, meningioma, fibrous dysplasia, and paraganglioma. Sixty-eight patients had malignant tumors, 32 of which were squamous cell earcinoma. Other malignancies included salivary carcinomas, basal cell carcinoma, neuroblastoma, melanoma, and several sarcomas. Unexpected findings were two metastatic carcinomas and five inflammatory lesions. Nearly 1500 intraoperative consultations were performed to establish resection margins and less commonly to confirm the diagnosis. The discrepancy rate between the intraoperative and final diagnosis was 1.8%. Immunohistochemistry and/or electron microscopy was utilized in 44% of the specimens to confirm the diagnosis. Surgical pathology is an essential ingredient to a successful skull base surgery program. Pathologists are involved in both pre- and intraoperative decisions. The diversity of lesions that arise from the skull base often has overlapping histologies that require careful attention to morphology and the use of ancillary studies for accurate diagnosis. The need for frequent intraoperative interpretations contributes to the significant challenge for the surgical pathologist.