Oxaliplatin is a third-generation platinum compound that has shown a definite role in the management of colorectal cancer (CRC). Oxaliplatin in combination with fluorouracil and leucovorin in the FOLFOX4 regimen represents a new standard of treatment in the adjuvant setting as well as for the metastatic disease. The combination of oxaliplatin with capecitabine in the XELOX regimen has been demonstrated to be not inferior to FOLFOX4 in metastatic patients, and it is under evaluation, with or without bevacizumab, in the post-surgical management of resected patients. FOLFOX4 and XELOX regimens represent a backbone on which to add new targeted drugs. Indeed, the combination of bevacizumab with either FOLFOX4 or XELOX significantly prolonged the progression-free survival and overall survival in comparison with FOLFOX4 or XELOX combined with placebo in metastatic CRC patients, while FOLFOX4 plus cetuximab produced a significantly greater activity than FOLFOX4 alone in metastatic CRC patients with K-RAS wild type.