Gastric cancer is a highly heterogeneous disease, displaying a complex genomic landscape and an unfavorable outcome with standard therapies. Based on distinctive genomic alterations, novel targeted agents have been developed with the aim of personalizing treatments and improving patient outcome. However, a subgroup of patients is primarily treatment-resistant, and even in the initially sensitive population, secondary resistance emerges, thus limiting therapeutic benefit. In this review, we summarize the clinical data about standard targeted agents in gastric cancer, specifically anti-HER2 treatments and antivascular therapies. We also illustrate the available evidence regarding molecular mechanisms of resistance to these agents and we discuss potential strategies for new targeted treatments that could overcome such resistance.