Cellular levels of H1 and core histone mRNAs have been examined in exponentially growing HeLa S3 cells as a function of DNA synthesis inhibition under varying concentrations of three DNA synthesis inhibitors. Total cellular histone mRNAs were analyzed by Northern blot hybridization, and their relative abundance was shown to be stoichiometrically and temporally coupled to the rate of DNA synthesis. In the presence of cytosine arabinoside, hydroxyurea, or aphidicolin, a rapid, proportionate decrease of histone mRNA levels resulted in an apparent mRNA half-life of less than 10 min. Using inhibitors of transcription and translation, we show that transcription is not necessary for the coordinate decrease of histone mRNA levels that occurs when DNA synthesis is inhibited. When protein synthesis is inhibited by addition of cycloheximide, core and H1 histone mRNAs do not decrease in parallel with reduced rates of DNA synthesis but instead are stabilized and accumulate with time, thus uncoupling histone mRNA levels and DNA replication. These last observations suggest that protein synthesis, either of histones or of some unidentified regulatory molecules, is required for the stoichiometric turnover of H1 and core histone mRNAs coordinate with reduced rates of DNA synthesis.