To determine the genetic elements required for modulation of ornithine decarboxylase (ODC) activity in response to cell growth or treatment with serum or with tetradecanoyl phorbol acetate, ODC-deficient cells were transfected with a series of recombinant DNAs encoding mouse ODC. All of the transfected cells expressing an intact mouse ODC protein displayed regulation of ODC activity, including those expressing a construct deprived of all ODC-specific sequence information except the protein-coding region. ODC mRNA changed much less than enzymatic activity. A mutation of the protein-coding region that converted ODC from an unstable to a stable intracellular protein attenuated the regulatory response. We conclude that post-transcriptional events associated with ODC degradation dominate the response to these stimuli.