Translational biomarkers are often expected to reduce uncertainty between preclinical experiments and early human development, yet many fail precisely at the point where they are asked to carry an inference across biological, analytical, pharmacological, or clinical boundaries. This review argues that biomarker failure is rarely a single event. A marker can be analytically robust but biologically nonrepresentative, transferable across assays but not across species or disease states, exposure-responsive without reflecting target-site pharmacology, or mechanistically proximal without informing a clinically meaningful endpoint. The central problem is therefore not biomarker presence or absence but whether each inferential link needed for a specific development decision remains valid. The review separates six recurrent failure classes: inadequate biological validity in the preclinical model, species or disease-context nontransferability, assay non-equivalence, exposure–biomarker discordance, tissue-compartment mismatch, and absence of decision-relevant endpoint linkage. It further distinguishes genuine biomarker failure from situations in which apparently discordant data are explained by temporal hysteresis, tissue retention, alternative context of use, or a correctly measured pharmacodynamic effect that is simply insufficient to produce clinical benefit. This boundary-based view supports a more disciplined strategy for early development: specify what a biomarker is intended to establish, identify the biological and measurement assumptions required for that inference, and falsify those assumptions before escalating confidence.
IJPRAS
