The overexpression of the human epidermal growth factor receptor type 2 (HER-2) is an independent prognostic factor of poor outcome in patients with breast cancer. Two compounds have been registered for HER-2-positive tumour treatment: trastuzumab, a humanised antibody directed against the HER-2 extracellular domain, and lapatinib, a small molecule acting as a dual EGF-R and HER-2 tyrosine kinase inhibitor. Although both drugs improve progression-free survival, many patients' tumours will exhibit primary resistance, or develop secondary resistance, to anti-HER-2 therapies. The recent significant improvement of survival gained with pertuzumab (an antibody disrupting dimerisation of the receptor) or trastuzumab emtansine (T-DM1, a cytotoxic drug vectored by trastuzumab binding) opened the way for new registrations. This review describes the molecular mechanisms by which tumour cells may adapt to and evade HER-2 inhibition by HER-2-targeted therapies and discusses strategies to prevent and overcome resistance to trastuzumab and lapatinib. These strategies may include the establishment of predictive markers, exploration of combination therapies and modulation of nodal targets.