Eleven years after Trastuzumab was approved for use in the treatment of early stage human epidermal growth factor receptor positive breast cancer (HER2+) its clinical benefit has been demonstrated in short and long term follow up studies. The cost-effectiveness of the therapy in this context remains the subject of debate with a wide range of Incremental Cost Effectiveness Ratios (ICERs) reported in the literature. While several reviews of the literature have been undertaken these have not provided a critical analysis of the factors that might underlie this heterogeneity. In this review we provide a critical overview of the literature and discuss potential sources of heterogeneity in reported ICERs. We identify gaps in the current literature and provide a rationale for filling these gaps.