Metastatic or unresectable esophageal and gastroesophageal junction adenocarcinoma represent a devastating disease with 5-year survival rate of <5%. Although cytotoxic chemotherapy with platinum doublet based regimens is initially effective, patients inevitably progress. Patients often decline rapidly after this initial progression, making later lines of therapy a challenge to successfully administer. There have been multiple efforts to incorporate biologic agents, targeting pathways known to be dysregulated in esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, into existing chemotherapy backbones. Other than therapeutics targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor receptor (VEGFR), other strategies have failed. Given the mixed success of biologic agents, along with the promise of immunotherapy to generate durable and sometimes complete responses, immune-agent based trials are a major area of interest for patients with this disease. Checkpoint inhibitors blocking programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated modest single-agent efficacy in patients with progressive esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma. However, other approaches such as novel checkpoint combinations, vaccine-based approaches and autologous T cells hold more promise to change the trajectory of disease.