Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a transcriptional coactivator that favorably affects mitochondrial function. This concept is supported by an increasing amount of data including studies in PGC-1 alpha gene-deleted mice, suggesting that PGC-1 alpha is a rescue factor capable of boosting cell metabolism and promoting cell survival. However, this view has now been called into question by a recent study showing that adeno-associated virus-mediated PGC-1 alpha overexpression causes overt cell degeneration in dopaminergic neurons. How is this to be understood, and can these seemingly conflicting findings tell us something about the role of PGC-1 alpha in cell stress and in control of neuronal homeostasis?.