The pharmacological characteristics of oxaliplatin make it one of the better chemotherapeutics to be combined with novel molecular-targeted anticancer treatments for the therapy of gastrointestinal tumors. The purposes of this review article are to report the preliminary data of combined therapy of oxaliplatin with inhibitors of angiogenesis or epidermal growth factor receptor and to suggest novel oxaliplatin-based therapeutic strategies. It is hypothesized that well designed, personalized, molecular-based treatments may improve the efficacy of oxaliplatin for the treatment of colorectal, gastric and pancreatic cancer. It is mandatory to rationalize such an approach by adequate determination of predictive surrogate biomarkers of response related to the targets in each single tumor against which therapy is aimed, using standardized assays and quality control.