While both prognostic and predictive cancer biomarkers predict clinical outcome, the term ‘predictive biomarker’ is reserved for the association of a specific therapy with a specific clinical outcome. The advent of genomic signatures and next generation sequencing as candidate predictive biomarkers has led to lengthy and expensive processes for biomarker qualification. The urgency to bring novel predictive cancer biomarkers to practice faster and cheaper requires strategies to lower the bar to biomarker implementation. Three strategies are suggested: identify biomarkers closely coupled to biologic mechanism associated with the clinical endpoint and scalable from cells to humans; identify biomarkers that can be reliably detected and quantified; and assess biomarkers by capacity to reduce toxicity as well as to increase therapy efficacy. Biomarker selection directly and closely related to production of end points by biologic mechanism demonstrated by a ladder of evidence should require less burden of proof clinically than biomarkers that are merely associative.