CRX (OTX3) is a transcription factor of the OTX homeobox family, whose expression and function is essential for the development and differentiation of retinal and pineal cells. Among human cancers, CRX seems to be selectively expressed only by retinoblastomas and pineal tumors. In our immunohistochemical analysis, performed on 89 primary and metastatic central nervous system tumors, we found that CRX is strongly expressed by normal pineal tissue as well as by pineal parenchymal tumors. Other than pineal tumors, we observed CRX positivity not only in a few medulloblastomas but also in atypical teratoid/rhabdoid tumors and in small cell lung carcinoma metastasis, in which photoreceptor differentiation has not been reported so far. In conclusion, CRX could represent a potential routine immunohistochemical marker in surgical neuropathology for the differential diagnosis of tumors of the pineal region. However, owing to the significant percentage of negative cells in some pineal tumors of our series, CRX negativity does not definitively rule out the diagnosis of a pineal parenchymal tumor, particularly in case of small biopsy specimens.