A series of pilot studies have been conducted in an attempt to isolate and purify the important biological mediators which cause the marked but self-limited increase in cellular activity following tissue injury. Wounds made in guinea pigs were excised after three to five days and homogenized. These were tested for biological activity by measuring their influence on the outgrowth of fibroblasts from explants in vitro and their ability to produce an inflammatory response in vivo. Lysosomal fractions from healing wounds, neutrophils, and liver were found to be highly active. Lysosomal granular fractions were further extracted by repeated freeze-thawing, homogenization, and precipitation of the soluble material with increasing concentrations of cold ethanol. Precipitates obtained between 50% and 70% concentration contained the active material. Our findings suggest that cellular proliferation at sites of tissue injury results from release of biologically active mediators from lysosomes of injured or dead cells, including neutrophils sequestered in injured tissues.