In the era of targeted cancer therapy, immunohistochemistry (IHC) and gene alterations must be detected by pathologists for diagnostic, prognostic, and predictive purposes. The interdisciplinary ONCOTEAM should be able to decide the best therapeutic approach for any patient based on their clinicopathologic factors, histologic aspects, IHC profile, and DNA/RNA information. This chapter was based on data from the literature and experience of two pathologists in the daily diagnosis of cancer. Tissue assessment (from surgical or endoscopic removal and grossing in the Pathology Department to histology), IHC, and molecular determinations were discussed for the most common cancer types that are eligible for molecular targeted therapy. This chapter aims to serve as a guide for using tissue to confer its best predictive value. For any cancer, the particularities of tissue examination and pre-analytical steps were also presented.