Unconventional　protein　secretion　(UcPS)　encompasses　diverse　non-canonical　cellular　export　mechanisms　that　operate　independently　of　the　classical　secretory　pathway,　representing　a　crucial　cellular　response　to　various　physiological　and　pathological　conditions.　This　comprehensive　review　synthesizes　current　understanding　of　UcPS　mechanisms,　particularly　focusing　on　their　roles　in　disease　pathogenesis　and　progression.　Recent　advances　in　proteomics　and　cellular　biology　have　revealed　that　UcPS　facilitates　the　secretion　of　various　biomedically　significant　proteins,　including　inflammatory　mediators,　growth　factors,　and　disease-associated　proteins,　through　multiple　pathways　such　as　membrane　translocation,　secretory　lysosomes,　and　membrane-bound　organelles.　Notably,　dysregulation　of　UcPS　mechanisms　has　been　implicated　in　various　pathological　conditions,　including　chronic　inflammation,　neurodegenerative　disorders,　and　malignant　transformation.　We　critically　evaluate　the　molecular　machinery　governing　UcPS,　its　regulation　under　cellular　stress,　and　its　contribution　to　disease　mechanisms.　Furthermore,　we　examine　emerging　therapeutic　strategies　targeting　UcPS　pathways,　highlighting　both　opportunities　and　challenges　in　developing　novel　interventional　approaches.