Pemetrexed is a multi-targeted anti metabolite that inhibits several key folate-dependent enzymes in the thymidine and purine biosynthetic pathways, including thymidylate synthase. It is currently approved for use in patients with non-small cell lung cancer and malignant mesothelioma. The sporadic and unpredictable occurrence of haematological toxicities of pemetrexed leading to potentially life threatening complications during the early developmental phase, prompted urgent need to identify potential predictive factors for haematological toxicities from pemetrexed. There is a well established association between elevated plasma homocysteine concentration, which is indicative of impaired functional folate status, and increased risk of haematological toxicity from pemetrexed. The decrease in incidence of toxicity after vitamin supplementation confirms the importance of functional folate status as a predictor for haematological toxicity. We review other factors that have a documented impact on haematological toxicity, including pemetrexed schedule, and pharmacokinetic parameters that are indicative of the extent of drug exposure. Further potential factors are explored in this review, such as the genotype of the pemetrexed metabolising enzymes and varying incidences of polymorphism of these genotypes in different ethnic groups that may account for the ethnic differences in neutropenic response to pemetrexed.