The administration of pemetrexed requires routine supplementation with vitamin B12 and folate, even if blood concentrations are normal, in order to mitigate its hematologic toxicity. Emerging data suggest that such premedication can be initiated less than 1 week before starting chemotherapy. The current available data on later administration of vitamin B12 in patients with thoracic tumors are placed into a general context, and the possible role of such strategy in the era of immunooncology is discussed.