To review the time course of muscle mechanics, etiological factors, and molecular mechanisms contributing to the development of postvoid residual urine (PVR), with an emphasis on transcriptomic changes in detrusor underactivity secondary to bladder outlet obstruction (BOO). PVR, the volume of urine remaining in the bladder after micturition, is a key marker of lower urinary tract dysfunction. While often overlooked in routine assessment, it may signal underlying BOO or detrusor underactivity and is associated with serious complications. PVR, bladder physiology and mechanics, and BOO-associated molecular changes were integrated with mRNA expression data from patients with bladder outlet obstruction, as well as from short- and long-term obstructed rat bladders from our own laboratory. Efficient voiding depends on tightly coordinated neural and muscular activity; disruption by elevated outlet resistance, impaired detrusor contractility, or failed coordination can produce residual urine. Chronic BOO and detrusor underactivity are interlinked, with chronic obstruction initiating time-dependent compensatory mechanisms, but ultimately the bladder decompensates. Transcriptomic studies in humans reveal fibroblast-macrophage-epithelial crosstalk driving extracellular matrix remodeling, inflammation, and tissue repair, with conserved molecular pathways across species, including transforming growth factor beta, nuclear factor-kappa B, and phosphoinositide 3-kinase/protein kinase B signaling. Rat models highlight Cthrc1 as a regulator of smooth muscle proliferation after denervation and implicate hypoxia-responsive transcription factors. PVR arises from a multifactorial interplay of timedependent mechanical, myogenic, and neurogenic factors, underpinned by conserved molecular pathways. Molecular diagnostics integrating messenger RNA/microRNA signatures hold promise for early detection of detrusor decompensation, enabling targeted interventions to preserve bladder function and prevent complications.