Recent experimental evidence has led to the Interpretation that “enamel‐like” material is deposited along the forming mouse molar root surface by cells of Hertwig's epithelial root sheath (HERS cells) and that this material is integral to the developmental program for cementogenesis. The experimental strategy described in this study was to examine selected developmental stages of root formation for mouse first and second mandibular molars in order to localize the cellular sites ofamelogeningene transcripts using high resolutionin situhybridization. Amelogenin is the major structural protein of coronal enamel and is highly conserved among mammalian species at the DNA and amino acid sequence level. Within the limits of sensitivity forin situhybridization and utilizing either cRNAs or oligodeoxynucleotide probes, we were unable to localizeamelogenintranscripts within HERS cells from selected developmental stages associated with mouse molar root formation. In contrast, previous studies using antipeptide antibodies have provided immuno‐histochemical localization of amelogenin domains in HERS cell‐derived products. For these HERS cell‐derived proteins to contain both amelogenin epitopes and yet fail to yield nucleic acid hybridization Signals suggests that either gene rearrangement and/or alternative processing of messenger RNAs from the structural gene locus operate to produce immunologically related motifs sharing insufficient complementarity at the nucleotide level to permit efficient detection by hybridization. It is postulated that HERS cells synthesize proteins which contain amelogenin domains and that these proteins participate during cementogenesis. However, these enamel‐related proteins are neither identical to, nor collinear with coronal canonicalamelogen