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Colorectal cancer (CRC) remains one of the most common malignancies in the world. Development of resistance to conventional therapies is frequently observed in advanced stages of the disease and frequently involves MAPK signaling. Recent studies identified p38a. MAPK as a mediator of resistance to irinotecan and 5-fluorouracil in CRC. Our genetic and pharmacologic studies revealed that p38a is required to maintain CRC cell metabolism, as its inhibition leads to Fox03A activation, autophagy, cell death, and tumor growth reduction both in vitro and in preclinical mouse models. Furthermore, our data show that p38 is activated in response to cisplatin treatment and mediates chemoresistance in HT29-xenografted tumors. MEKl inhibition has been found to reduce CRC cell proliferation in vitro and to decrease tumor growth in xenograft models and we recently reported that MEK-ERKl/2 inhibition is followed by over-activation of the p38 MAPK pathway. We found that p38a and MEK combined inhibition specifically induces apoptosis by enabling TR. Aa signaling propagation through t-Bid and caspase 3, and fosters cell death in CRC cells. Sorafenib is reported to inhibit nine protein kinases, including BRAF, VEGF and the DGF-out conformation state ofp38a. Our results show that the SB202190 (type I p38a inhibitor) and Sorafenib (type II p38a inhibitor) synergize at the molecular and biqlogical level enhancing tumor growth inhibition and induction of apoptosis in CRC both in vitro and in vivo. The combined use of SB202190 and PD0325901 (MEKl inhibitor), Sorafenib or Cisplatin significantly reduced tumor growth by inducing a higher degree of apoptosis compared to each single treatment. Our data validate in vivo the combined inhibition of the p38a. and ERK pathways or their association with chemotherapy as a promising approach to treat CRC. Moreover, they suggest that the phosphorylation status of p38 MAPK may be a marker of resistance in CRC.