Vascular endothelial growth factor (VEGF) overexpression and increased angiogenesis have been proposed as having biologic importance in germ cell tumors (GCT). We conducted a single-institution phase II trial of sunitinib, an oral inhibitor of the VEGF receptor, in patients with relapsed or refractory GCT. A Simon's two-stage design was used to determine the number of patients for enrollment. Responses were assessed using a modified version of Response Evaluation Criteria in Solid Tumors (RECIST), taking into account tumor marker changes. Dose modifications were made according to a nomogram for adverse events. Ten patients were enrolled. The first five received sunitinib 50 mg for four consecutive weeks, followed by a two-week break (4/2). Since four of five treated on this schedule had some tumor marker decline during the four-week "on" period, with subsequent rise during the two-week break, the dose was changed to 37.5 mg continuously for patients six to ten. However, only marker stabilization (no declines) was seen. Overall, there were no objective responses: Five had stable disease and five progressive disease (PD). Sunitinib was well tolerated; only one patient required a dose reduction due to grade 3 mucositis. Two patients experienced tumor-related hemorrhage (grade 3 and grade 1). All patients developed PD within three cycles. Sunitinib is well tolerated, but at standard doses, does not demonstrate significant activity in highly refractory GCT. Correlation between sunitinib treatment and tumor marker changes on the 50 mg 4/2 schedule suggest some pathways targeted by sunitinib (ie, angiogenesis) may be important to GCT biology.