Programmed cell death (apoptosis) safeguards tissue homeostasis, and its dysregulation is a hallmark of cancer, neurodegeneration, and immune disorders. Detecting the earliest biochemical signatures of apoptosis therefore offers a route to sharper diagnosis, real-time therapy monitoring, and data-driven drug discovery. Electrochemical biosensors are uniquely suited to this task because they translate molecular recognition events into electrical signals that are rapid, miniaturizable, and inherently compatible with point-of-care formats. Yet their clinical translation is still limited by three persistent hurdles: (i) selective recognition in protein-rich or highly variable matrices, (ii) long-term signal stability under continuous operation, and (iii) a lack of unified analytical performance standards that hampers cross-platform benchmarking. This critical review charts the most recent material, biochemical, and microelectronic innovations that are beginning to erode these barriers, and identifies emerging strategiesfrom nanostructured electrode interfaces to signal processing that could propel electrochemical apoptosis sensing from proof-of-concept prototypes to reliable bedside tools. By aligning unresolved challenges with promising technological solutions, we aim to guide interdisciplinary efforts toward next-generation diagnostics capable of real-time apoptosis surveillance in complex biological settings.