A Viewpoint argues that ctDNA liquid biopsy can strongly predict colorectal cancer recurrence, but that the gap between prognostic performance and real-world clinical utility persists. The authors attribute the mismatch to misalignment of biology, testing timing, assay design, and trial methodology rather than a fundamental failure of ctDNA as a biomarker concept. The framing matters for trial strategy: it suggests that “more sensitive assays” alone may not close the clinical outcomes gap unless studies are designed to match the natural kinetics of tumor shedding and to avoid decision-making that is not biologically timed. The report underscores that ctDNA’s role may currently be best treated as prognostic while evidence accrues on when acting on results improves endpoints such as relapse-free survival and overall survival.