Biomarkers of tissue injury have evolved empirically over the last 50-100 years. With the advent of immunoassays and discovery tools such as RNA expression and proteomics, more systematic approaches to the discovery of biomarkers can be expected in the future. This review discusses the evolution of biomarkers of muscle, liver, heart and brain injury and illustrates that a modern discovery tool, such as mRNA profiling, would have predicted the biomarkers for cardiac injury (heart attacks) that actually evolved over 50 years by empiric approaches. We also discuss how novel biomarkers for brain injury were identified using RNA expression approaches. It is our prediction that there will be a growth in the number of valuable biomarkers for identifying cell and organ injury in the next 5-10 years.