Due to poor correlation between slice thickness and orientation, verification of medical imaging results by histology is difficult. Often validation of imaging findings of lesions suspicious for prostate cancer is driven by a subjective, visual approach to correlate in vivo images with histopathology. We describe fallacious assumptions in the correlation of imaging findings with pathology and identify the lack of accurate registration as a major obstacle in the validation of PET and PET/CT imaging in primary prostate cancer. Specific registration techniques that facilitate the most difficult part of the registration process--the mapping of pathology onto high-resolution imaging, preferably aided by the ex vivo prostate specimen--are discussed.