We previously identified four nuclear genes (caf1+ to caf4+) in Schizosaccharomyces pombe, mutations in which can confer caffeine resistance. Here we report the cloning and sequencing of caf1+, caf2+ and caf4+. All three genes are allelic to genes (hba1+, crm1+ and trr1+, respectively) involved in multidrug resistance mechanisms or in stress response systems. In agreement with this the caffeine-resistant mutants caf1(hba1)-21, caf2(crm1)-3 and caf4(trr1)-83 are also resistant to brefeldin. Disruption of caf1(hba1)+ and caf4(trr1)+ makes cells sensitive to high pH. The overlapping ranges of pleiotropic effects and the genetic interaction detected between caf1(hba1)+ and caf2(crm1)+ suggest that the three genes function in interlinked systems.