ObjectiveTo summarize the progress in mechanisms of resistance to trastuzumab in treating human epidermal growth factor receptor 2 (HER2)-positive breast cancer. MethodsBy searching Pubmed and CNKI, the literatures of mechanisms of resistance to trastuzumab in treating HER2-positive breast cancer were reviewed. ResultsThe possible mechanism of resistance to trastuzumab are thought to include HER2 gene amplification and high protein expression; impaired access of trastuzumab to HER2; bidirectional crosstalk between ER and HER2; HER2 downstream signal transduction pathway activation; expansion expression of other RTKs and membrane-associated receptors; alterations in apoptosis and cell cycle control as well as multi-gene mutation, etc. ConclusionsMechanisms of trastuzumab resistance in HER2-positive breast cancer is complicated, a better understanding will be achieved by comprehensive analysis of existing possible mechanisms. The outcome of HER2-positive breast cancer patients who developed resistance to trastuzumab will be improved by appropriate multi-target regime.