Abstract: Mitochondria are essential organelles that play a central role in cellular metabolism and physiology. Their broad range of functions include supplying energy, regulating signaling pathways, and maintaining control of cell proliferation and apoptosis. As defective mitochondria can perturb cellular homeostasis, quality control mechanisms have evolved to preserve mitochondrial fidelity in response to stress and aging (Palikaras et al., 2018). Persistent defects, however, trigger elimination of the entire organelle by an evolutionarily conserved set of cellular processes that specifically remove dysfunctional or surplus mitochondria. This selective degradation of the mitochondria through autophagy, termed mitophagy, is important in fine-tuning mitochondrial number, integrity and ultimately function. Mitophagy impairments can cause progressive accumulation of defective mitochondria, particularly in terminally differentiated post-mitotic cells, like neurons, which remain alive and functional for decades. The ensuing rise in oxidative stress and aggregation of proteins is likely to contribute to tissue damage linked to a broad spectrum of pathological conditions, such as neurodegenerative diseases, myopathies, inflammation, metabolic disorders and cancer (Palikaras et al., 2018). Despite major milestones in the mitophagy field within the last decade, important questions regarding the in vivo role of specific components, their interplay in different mitophagy pathways and their spatiotemporal regulation in distinct physiological and pathological contexts remain unanswered (Pickles et al., 2018). This short perspective will focus on recent advances towards elucidating the molecular mechanisms that govern mitophagy and downstream cell fate decisions, with specific attention to the potential contribution of the co-chaperone Bcl-2-associated athanogene (BAG) protein family focusing on BAG5 in Parkinson’s disease (PD), ischemia and aging-associated inflammation.