The rapid evolution of high-throughput technologies and computational biology has revolutionized our understanding of complex human pathologies. Today, integrating bioinformatics and multi-omics approaches, including genomics, transcriptomics, epitranscriptomics, and metabolomics, is essential for deciphering intricate molecular mechanisms, mapping microenvironment remodeling, and identifying novel biomarkers. This Special Issue, titled "Bioinformatics and Multi-Omics Approaches in Modern Medicine and Oncology," aims to gather cutting-edge research that leverages computational tools, network medicine, and machine learning to advance precision medicine. We welcome original research articles, reviews, and meta-analyses exploring the functional landscapes of non-coding RNAs, epigenetic modifications, and cellular heterogeneity in both neoplastic and non-neoplastic diseases. Key areas of interest include, but are not limited to, multi-omics data integration for diagnostic or prognostic modeling, single-cell analysis of tumor microenvironments, and causal inference via Mendelian randomization. By bridging the gap between data science and clinical application, this collection seeks to highlight transformative insights that drive therapeutic innovation. We cordially invite researchers and clinicians to contribute their latest findings to this timely and impactful issue.