Variable expression of the HER2 receptor has been implicated in the pathogenesis of a number of malignancies. Many therapeutic modalities have been devised that target the receptor and downstream molecular pathways. The humanized monoclonal antibodies trastuzumab and pertuzumab bind epitopes on the extracellular domain, resulting in cell growth inhibition though a number of proposed mechanisms. Peptidomimetic agents represent short amino acid sequences containing structural features of the antibody complementarity determining regions (CDRs), and appear to have similar inhibitory properties in experimental models. RNA aptamers are ribonucleotide sequences that also exhibit complementarity with extracellular epitopes and lead to growth inhibition. Recent data suggest a synergistic interaction of HER2 epitope-targeting agents when used in combination.