mRNA is a critical biomolecule involved in the manifestation of the genetic code into functional protein molecules. Its critical role in the central dogma has made it a key target in many studies to determine biomarkers and drug targets for numerous diseases. Currently, there is a growing body of evidence to suggest that RNA molecules around the size of full-length mRNA transcripts can be assayed in the supernatant of human urine and urinary extracellular mRNA could provide information about transcription in cells of urogenital tissues. However, the optimal means of normalizing these signals is unclear. In this paper, we describe relevant first principles as well as research findings from our lab and other labs toward normalization of urinary extracellular mRNA.