Esophagogastric cancer is associated with rising incidence and high mortality. Nearly 40% of patients have metastatic disease at the time of diagnosis with poor 5-year overall survival. The treatment of squamous cell carcinoma of the esophagus and gastroesophageal adenocarcinoma has started to bifurcate in recent years, owing to the evolving understanding of the biologic and genomic characteristics of these tumors. Incorporation of HER2-directed therapy in the form of monoclonal antibody and antibody-drug conjugate is now standard of care for patients with HER2-positive disease. The addition of immune checkpoint inhibitors to the therapeutic landscape of metastatic esophagogastric cancer is associated with modest improvement in overall survival, and definition of predictive biomarkers of response to checkpoint inhibition remains imprecise. A number of therapeutic targets including FGFR2b, Claudin 18.2, DKK-1, and DNA repair defects are being explored in clinical trials. Similarly, combination immunotherapy and novel HER2-targeting agents, such as bispecific antibody and small-molecule inhibitors, are at various stages of clinical development. Despite the progress made in the field of targeted therapies and checkpoint inhibition, chemotherapy remains an integral part of treatment of metastatic esophagogastric cancer but is associated with considerable toxicity. Clinical trials focusing on minimizing toxicity of currently available therapeutic agents, development of novel biomarker-driven treatment strategies, and overcoming resistance to immune checkpoint inhibition will define the future of this traditionally indelible disease.