Metastasis is the principal cause of cancer mortality and arises when tumor cells acquire the ability to invade surrounding tissues, enter circulation, survive hemodynamic and immune stresses, and colonize distant organs. This metastatic cascade is highly inefficient, with only a minute fraction of circulating tumor cells forming macrometastases. EMT enables tumor cells to lose polarity, remodel the cytoskeleton, and gain motility; it also promotes immune evasion through cytokine secretion, PD-L1 upregulation, and reduced MHC-I expression. EMT and its reverse process, MET, operate within a landscape of strong transcriptional, metabolic, and epigenetic plasticity that is largely nongenetic in origin. Metastatic success depends on tumor microenvironmental compatibility, tissue-specific metabolic niches, stromal cell interactions, and immunological conditioning. Aging, chronic inflammation, stress, and neural-endocrine signals further remodel metastatic niches and influence dormancy-reactivation cycles. Brain metastases exemplify a uniquely selective niche that imposes convergent epigenetic programs required for blood-brain barrier traversal and neural microenvironmental adaptation. Advanced cancers also induce systemic metabolic dysregulation and physical tissue disruption. Tumor-derived cytokines, hormones, and extracellular vesicles trigger cachexia, a multiorgan wasting syndrome driven by accelerated muscle catabolism, adipose tissue browning, and neuroendocrine dysfunction. Ultimately, metastatic disease causes death through organ failure, thromboembolic events, infections, and widespread metabolic collapse rather than tumor burden alone.