Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor beta superfamily. GDF-15 expression is dramatically upregulated during acute brain injury, cancer, cardiovascular disease, and inflammation, suggesting its potential value as a disease biomarker. It has been suggested that GDF-15 has neurotropic effects in the nervous system. Our studies showed that GDF-15 modulated the expression of neuronal K+ and Ca2+ ion channels and increased the release of excitatory transmitter in the medial prefrontal cortex of mice. GDF-15 is also involved in the complex modulation of cancer and cardiovascular disease. Here, we reviewed studies involving the modulation of GDF-15 expression and its mechanisms, the primary pathological and physiological functions of GDF-15 in neurological and cardiovascular systems, and its role in cancer progression. The biological effects and the values of GDF-15 in basic research and clinical applications were also addressed.