A Saccharomyces cerevisiae mutant, lis1-1, hypersensitive to Li+ and Na+ was isolated from a wild-type strain after ethylmethane sulfonate mutagenesis. The rates of Li+ and Na+ uptake of the mutant are about 3-4-times higher than that of the wild-type; while the rates of cation efflux from the mutant and wild-type strains are indistinguishable. The LIS1 was isolated from a yeast genomic library by complementation of the cation hypersensitivity of the lis1-1 strain. LIS1 is a single copy, nonessential gene. However, the deletion of LIS1 from the wild-type results in a growth defect in addition to the cation hypersensitive phenotype. The order of increasing cation uptake rates of the wild-type and mutant strains, LIS1 < lis1-1 < lis1-delta 1::LEU2, correlates perfectly with the degree of cation hypersensitivity, suggesting that the cation hypersensitivity is primarily due to increased rates of cation influx. LIS1 encodes a membrane associated protein 384 amino acids long. Data base searches indicate that LIS1 is identical to ERG6 in S. cerevisiae which encodes a putative S-adenosylmethionine-dependent methyltransferase in the ergosterol biosynthetic pathway. Cell membranes of lis1 (erg6) mutants are known to be devoid of ergosterol and have altered sterol composition. Since membrane sterols can influence the activity of cation transporters, the increased cation uptake of the lis1 mutants may stem from an altered function of one or many different membrane transporters.