In recent years, significant progress has been made in the diagnosis and treatment of gastrointestinal cancers. Researches and clinicians however are still faced with challenges, not the least is the detection and management of tumors with varied gene mutation status. Clarification of the molecular pathology of gastrointestinal cancers may improve treatment options as well as quality of life and the long-term survival of this patient class. Therefore, molecular-targeted therapies have emerged as clinically useful drugs for gastrointestinal cancers cure, and predictive biomarkers have been heralded as the way to develop the right drug for the right patient. Moving from such appealing molecular background, we wrote an overview of the main targeted therapies, with particular interest to monoclonal antibodies that have already been approved in clinical practice or are being tested in gastrointestinal cancers treatment.