Cell-free circulating DNA (cfDNA), released from dying cells, is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. We developed a method of detecting tissue-specific cell death in humans, based on tissue-specific methylation patterns of DNA circulating in plasma. We interrogated tissue-specific methylome datasets to identify cell type-specific DNA methylation signatures, and established a method to detect these in mixed DNA samples and in cfDNA isolated from plasma. Using this new type of biomarker it is possible to detect the presence of cfDNA fragments derived from multiple tissues in healthy individuals and in pathologies including cancer, myocardial infarction, sepsis, neurodegeneration and more. In the long run we envision this approach opening a minimally-invasive window for monitoring and diagnosis of a broad spectrum of human pathologies, as well as better understanding of normal tissue dynamics.