This review focuses on the pathogenesis of HER2-positive breast cancer, current standard treatments, the mechanisms of approved irreversible TKIs, key clinical trials, and the activity of irreversible TKIs in brain metastases to provide scientific evidence on the regimen of irreversible pan-HER TKIs plus chemotherapy for HER2-positive MBC patients. This evidence concerns the gene ERBB2 and breast carcinoma.