Brain metastases (BM) and leptomeningeal metastases (LM) are devastating neurologic complications. Pemetrexed is a multi-targeted anti-folate agent approved for treatment of nonsquamous non-small cell lung cancer but has anti-tumor activity in other solid tumors. We performed two trials using pemetrexed in patients with BM and LM to assess CSF penetration and anti-tumor activity. Patients were treated with intravenous pemetrexed at doses of 500 (n = 3), 750 (n = 3), 900 (n = 12) or 1,050 mg/m(2) (n = 3) every 3 weeks. Neuro-imaging was done every 6 weeks. Matched CSF and plasma samples were obtained serially from three patients with Ommaya reservoirs; the remaining patients had a single paired collection. Twenty-one patients (15 women and six men) with median age of 50 years and median KPS of 90 were treated. Primary tumors included breast (13), lung (4), colorectal (1), endometrial (1), esophageal (1) and pinealoblastoma (1). Nine patients had prior whole brain RT and median number of prior chemotherapies was two including prior methotrexate in four patients. Median pemetrexed doses administered was three (range 1-14). Responses included one partial response, ten stable disease and ten progressive disease. Median time to progression and survival was 2.7 and 7.3 months; PFS six was 22 %. No major toxicities were seen. Pemetrexed distributed from the plasma to the CSF within 1-4 h with the resulting CSF concentrations < 5 % of plasma. Pemetrexed was tolerated in solid tumor patients with CNS metastases. Limited anti-tumor activity was seen, which might have been due to low CSF concentrations, although some patients displayed prolonged benefit.