Cytarabine arabinoside (ara-C) is an antimetabolite used to treat hematologic malignancies. Resistance is a common reason for treatment failure with adverse side effects contributing to morbidity and mortality. Identification of genetic factors important in susceptibility to ara-C cytotoxicity may allow for individualization of treatment. We used an unbiased whole-genome approach using lymphoblastoid cell lines derived from persons of European (CEU) or African (YRI) ancestry to identify these genetic factors. We interrogated more than 2 million single nucleotide polymorphisms (SNPs) for association with susceptibility to ara-C and narrowed our focus by concentrating on SNPs that affected gene expression. We identified a unique pharmacogenetic signature consisting of 4 SNPs explaining 51% of the variability in sensitivity to ara-C among the CEU and 5 SNPs explaining 58% of the variation among the YRI. Population-specific signatures were secondary to either (1) polymorphic SNPs in one population but monomorphic in the other, or (2) significant associations of SNPs with cytotoxicity or gene expression in one population but not the other. We validated the gene expression-cytotoxicity relationship for a subset of genes in a separate group of lymphoblastoid cell lines. These unique genetic signatures comprise novel genes that can now be studied further in functional studies.