Mutations in K-Ras are observed in approximately 40% of colon tumours. This has significant implications for predicting likelihood of response to the antibody-based EGFR inhibitors, cetuximab and panitumumab, with K-Ras mutant patients now clearly shown to be inherently resistant to these agents. Alternative treatment strategies for K-Ras mutant patients are therefore urgently needed. Farnesyltransferase inhibitors, developed to inhibit K-Ras, have to-date been largely unsuccessful. However, a number of agents which target signaling components in the MAPK and PI3K pathways downstream of mutant K-Ras are currently being evaluated in clinical trials and will be discussed. A further clinical concern is that K-Ras wild type patients who initially respond to EGFR inhibitors eventually develop acquired resistance to these agents and experience tumour progression. Studies from the use of related agents in other disease settings as well as pre-clinical studies provide important insights into mechanisms by which this may occur. While no evidence presently exists for somatic mutations as a basis for acquired resistance to EGFR inhibitors in colon cancer, several studies implicate upregulation and signaling via other Her family members, c-Met, IGFR and Src. Upregulation of the pro-angiogenic factor, VEGF, is also a possible mechanism of acquired resistance. This review discusses drugs currently in clinical trials that may potentially achieve more efficient and prolonged targeting of the EGFR pathway by overcoming these mechanisms of resistance.