The number of cancer cases is expected to increase by 40% in 20 years and reach nearly 30 million new cases per year in 2040 [1]. Therefore, it is of utmost importance to get a grip on cancer prevention and early diagnosis. Colorectal cancer (CRC) is the third most commonly diagnosed and the second most deadly cancer worldwide [1]. Because it begins insidiously, 20% of CRC cases are not discovered until cancer has already outgrown the colon [2]. Detecting tumors at an early stage represents a major opportunity to reduce CRC morbidity and mortality and improve patient prognosis. Renal cell carcinoma is the ninth most common cancer worldwide, with an increasing incidence due to growing obesity rates, smoking and alcohol consumption. In most cases, renal cell carcinoma is diagnosed incidentally on imaging, and rarely presents with either classic symptoms such as hematuria and flank mass or paraneoplastic syndromes or varicocele in men [3]. 35% of renal cell carcinoma cases are detected at the metastatic stage, and no current screening test is available.Cell-free DNA (cfDNA) found in the bloodstream is primarily a byproduct of cell death in both normal and cancer cells [4]. Circulating DNA fragments are mainly short molecules with an average length of mononucleosome size that tend to be more fragmented in internucleosomal linkers and open chromatin regions. This leads to a biased, non-random fragmentation pattern [5]. Moreover, tumor-derived DNA fragments (ctDNA) tend to be shorter than the non-tumor cell-derived fraction, and constantly accumulating evidence suggests that cfDNA fragmentation may serve as a cancer biomarker at the whole-genome level [6, 7]. Some studies argue the presence of specific genomic regions with preferential tissue-specific or tumor-specific cfDNA fragmentation [8]. Recently, several groups have thoughtfully characterized open chromatin landscapes in human cancer [9, 10], allowing further extrapolations to the cfDNA fragmentation footprints [11]. Here, we focus on targeted high-resolution profiling of cancer-specific open-chromatin regions in cfDNA from the blood of healthy individuals and patients with colorectal and renal cancers. We demonstrate that the proposed approach can facilitate cancer detection.