Background: Circulating cell-free DNA (cfDNA) is a novel type of biomarker with a broad utility in diagnostic medicine, based on the release of DNA fragments from dying cells to the circulation. We developed an approach for identifying the tissue origins of cfDNA, using cell-type-specific DNA methylation patterns, based on a massive reference atlas of the genome-wide methylomes of multiple human tissues and cell types. Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. We demonstrated that brain cell death in CNS cancer can be detected by tissue-specific methylation patterns of circulating cfDNA. Methods: We developed a cocktail of brain-specific DNA methylation markers, and used it to assess the presence of brain-derived-cfDNA in the plasma of patients with brain metastasis. Results: We identified significantly elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA (p<0.0001) in patients with brain metastases (n=29) compared with cancer patients without brain metastasis (n=113). Conclusions: We show a new set of biomarkers to identify brain damage with high specificity and resolution. We detected brain (neurons, oligodendrocytes, astrocytes) cfDNA in the plasma of patients with brain metastasis. Cell-type-specific cfDNA methylation markers allow the identification of collateral tissue damage, reveals the presence of metastases, and potentially assist in early cancer detection.