The incidence of brain metastases from nonsquamous non-small-lung cancer is increasing as a result of superior imaging techniques for early detection of distant metastases. Although whole-brain radiation therapy and stereotactic radiosurgery along with systemic chemotherapy have shown to be effective in alleviating symptoms and improving outcomes, the approach to patients with asymptomatic brain metastases remains elusive. We explored the literature for a possible role of frontline systemic chemotherapy in asymptomatic brain metastases from nonsquamous non-small-lung cancer and found promising evidence that upfront systemic therapy with pemetrexed-platinum regimens might be a reasonable option for these patients and would forestall the need for upfront brain radiation therapy. More large-scale phase II and phase III clinical trials are needed to further investigate the frontline use of pemetrexed-platinum regimens in this setting.