Anti-VEGF (vascular endothelial growth factor) therapy with the monoclonal antibody bevacizumab can cause gastrointestinal (GI) perforations. In recent years it became apparent that GI perforations also occur during treatment with antiangiogenic tyrosine kinase inhibitors (TKIs). It is of clinical importance to consider (vague) abdominal complaints during antiangiogenic treatment as a sign of a GI perforation. To illustrate this serious complication, we report four cases of antiangiogenic treatment related GI perforations. In three cases this was due to antiangiogenic TKI treatment. Reported risk factors of GI perforations due to bevacizumab include the presence of a primary tumor in situ and recent history of endoscopy or abdominal radiotherapy. Pathology assessments of surgical removal of the perforated intestinal part reveal that perforations are predominantly seen at the tumor or anastomotic site, in case of carcinomatosis or diverticulitis or when GI obstruction or an intra-abdominal abscess is present. Whether the same risk factors may be involved in antiangiogenic TKI related GI perforations is unknown. The underlying mechanisms responsible for GI perforation during antiangiogenic treatment is unknown, but disturbance of host cell homeostasis of immune cells as well as platelet-endothelial cell interactions may play an important role. In conclusion, while clinical awareness that antiangiogenic treatment can cause GI perforations is critical for current medical practice, it is also very important to get more insight in its underlying mechanisms so that this life-threatening complication may be prevented in the near future.