Mismatch repair (MMR) proteins are capable of recognizing and processing not only single base-pair mismatches and insertion-deletion loops that occur during DNA replication, but also adducts in DNA resulting from treatment with cancer chemotherapy agents. MMR deficiency leads to microsatellite instability (MSI) and results in resistance to antimetabolites, alkylating and platinating agents, DNA minor groove binders, and inhibitors of topoisomerases. Therefore, anticancer agents that can be recommended for use in MMR deficient colorectal cancers are those that exert their cytotoxicity regardless of the MMR status. These include some alkylating drugs, brostacillin, gemcytabine, photodynamic therapy, taxanes. An approach that is currently receiving much attention is the use of agents such as 5-azacytidine, an inhibitor of the DNA methyltransferases, in combination with inhibitors of histone de-acetylation, to restore the MMR function. A strong anti-proliferative efficacy with a relatively low direct cytotoxicity, obtainable with oloumicine and roscovitine (selective cyclin-dependent kinases inhibitors) can represent a new expedient for the therapeutic treatment of MMR deficient colorectal cancers. The question of how MMR defects modulate the response to chemotherapeutics deserves further investigation, to enable a more aware choice of cancer treatment.