Members of epidermal growth factor receptor (EGFR) or ErbB receptor family play a critical role in a wide range of human cancers. In the past decade, there has been a remarkable progress in developing ErbB targeted therapeutics. However, a substantial portion of patients has non-responsive disease or subsequently shows evidence of tumour relapse following initial success with anti-ErbB agents. Improved insights into the biology of ErbB receptor family have led to more effective second- and third-generation anti-ErbB therapies. In this review, we have summarised salient features of the ErbB receptor physiology and highlighted key mechanisms involved in abnormal ErbB signalling in tumorigenesis. The rationale of anti-ErbB receptor therapies are outlined along with key mechanisms proposed for resistance to treatment as well as the current concept of combined anti-ErbB therapies. In conclusion, improved understanding of the molecular pathways that confer resistance to anti-ErbB therapeutics will be essential in minimising tumour resistance to ErbB targeted treatments.