Expression of the c-myc gene can be controlled by transcriptional or posttranscriptional mechanisms (or both), depending on the cell type and the growth conditions. An important mechanism of posttranscriptional regulation is modulation of cytoplasmic c-myc mRNA stability; normal human and murine c-myc mRNAs have cytoplasmic half-lives of 30 min or less. To elucidate the c-myc sequences which impart this unusually high rate of cytoplasmic transcript turnover, we have constructed various deletion and hybrid c-myc genes and analyzed the cytoplasmic stability of the mRNAs produced from them in stably transfected murine fibroblasts. The results indicate that sequences contained within the 5' and 3' ends of the c-myc transcript can affect cytoplasmic stability. Specifically, the 3' untranslated sequences of c-myc exon 3 are required for, but do not ensure, a high rate of transcript turnover in the cytoplasm. Exon 2 coding sequences do not seem to be involved, and exon 1 sequences at the 5' end of the transcript have only a small effect on cytoplasmic transcript stability. The sequences that are primarily responsible for the short c-myc RNA half-life were localized to a region of 140 bases in the 3' untranslated region.