Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new aetiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival, and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies.