The newly developed concept of oncogene addiction provides a rationale for the use of targeted therapies. In sharp contrast to the field of breast cancer treatment, attempts to target human epidermal growth factor receptor 2 (HER2) among gastric cancer (GC) patients have been unsatisfactory. The ToGA trial reported only a modest prolongation of progression‑free survival (PFS) with trastuzumab and the subsequent TYTAN and LOGiC trials failed to demonstrate any survival advantage with lapatinib. These results suggest that a response to the molecular‑targeted therapies is achieved in only a fraction of the patients; in addition, even responders may experience secondary resistance, with the efficacy of the treatment being decreased or abrogated over a short period of time. Considering the increased recognition of primary or acquired resistance, recent investigations on targeted therapies have been primarily focused on determining in advance the mechanisms that may mediate resistance to treatment and the methods through which such obstacles may be circumvented. The proposed molecules or mechanisms that may be responsible for the development of resistance to single HER2‑targeted therapy include a dimerization partner or crosstalk with HER2, such as HER3 and MET, as well as any subsequent activation of their downstream pathways, which exhibit a partial overlap with those of HER2. Furthermore, genetic alterations that stimulate the aberrant activation of the pathways downstream of HER2 may be the underlying mechanisms that restore prosurvival signaling. These mechanisms generate a complex signaling network with a significant potential for signal amplification and diversification. Although in the early stages of description, several compounds have been suggested as next generation treatments for GC, with expectations for their delineating the function of such receptors or molecules, with subsequent contributions of specific survival signaling blockades. This review focuses on the current achievements of anti‑HER2 therapies in GC and the plausible mechanisms of resistance to these therapies. Elucidating these mechanisms of resistance may provide valuable information pertinent to the design of future strategies to improve molecular‑targeted therapies.