Between 2005 and 2008, we conducted separate phase II clinical testing of three distinct anti-VEGF therapies for patients with relapsed/refractory CLL. Collectively, 46 patients were accrued to trials of single-agent anti-VEGF antibody (bevacizumab, n = 13) or one of two receptor tyrosine kinase inhibitors (AZD2171, n = 15; sunitinib malate, n = 18). All patients have completed treatment. Patients received a median of two cycles of bevacizumab, AZD2171, or sunitinib malate. All three trials were closed early due to lack of efficacy. No complete or partial remissions were observed. Individually and collectively, these studies indicate that single-agent anti-VEGF therapy has minimal clinical activity for patients with relapsed/refractory CLL.