This Reprint of the IJMS Special Issue "Circulating Non-Coding RNAs as Diagnostic and Prognostic Markers of Human Diseases" presents eight original research papers and five reviews that advance our diagnostic, prognostic, and mechanistic understanding of circulating non-coding RNAs (c-ncRNAs). The collection emphasizes the remarkable stability of c-ncRNAs in biofluids such as blood and urine, their tissue- and disease-specific expression profiles, and their growing promise in non-invasive liquid biopsy for precision medicine, spanning early detection, risk assessment, and therapeutic monitoring. Featured studies explore early lung cancer prediction in COPD via miR-206 and miR-1246; risk stratification in atrial fibrillation using miR-411-5p; the differentiation of coronary artery aneurysmal disease through miR-451a and miR-328-3p; the staging of mycosis fungoides by plasma miR-146a and miR-155; and asthma phenotyping associated with hsa-miR-26a-1-3p and hsa-miR-376a-3p. Additional research investigates NAFLD diagnostics using serum miRNA ratios and provides mechanistic insight into muscle development via circTTN. The reviews synthesize advances on c-miRNAs in osteoarthritis, miRNA and exosomal miRNA dysregulation in cholesteatoma, therapeutic biomarkers in asthma, and post-SARS-CoV-2 cardiovascular alterations, highlighting broad clinical relevance across oncologic, cardiovascular, metabolic, and inflammatory disorders. Collectively, these contributions underscore methodological progress toward standardization and position c-ncRNAs at the forefront of minimally invasive diagnostics and personalized therapy.

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