<p>Anoikis is a programmed cell death pathway triggered by cell detachment from the extracellular matrix, playing an essential role in maintaining tissue homeostasis and preventing aberrant cell colonization. The acquisition of anoikis resistance by tumor cells is a prerequisite for distant metastasis and a major contributor to therapeutic failure in cancer treatment. This review systematically summarizes the molecular mechanisms governing anoikis and the core pathways through which tumor cells evade this form of cell death. The precise regulation of anoikis depends on the integration of apoptotic signals by Bcl-2 family proteins, which orchestrate three major signaling axes, the extrinsic death receptor pathway, the intrinsic mitochondrial pathway, and the caspase-independent pathway. Tumor cells develop resistance to anoikis through diverse mechanisms, including epithelial-mesenchymal transition (EMT), remodeling of the tumor microenvironment, concentration-dependent modulation by reactive oxygen species (ROS), autophagy and metabolic reprogramming, coordinated activation of multiple signaling cascades, and regulatory networks involving non-coding RNAs. Furthermore, this review discusses current therapeutic strategies targeting anoikis resistance, including combination therapy, gene therapy, and targeted therapy, and outlines future research directions. A deeper understanding of the molecular networks and regulatory mechanisms underlying anoikis resistance will provide a theoretical foundation for developing novel interventional strategies to counteract tumor metastasis.</p>