Peroxisomes are ubiquitous and highly dynamic organelles that play a central role in the metabolism of lipids and reactive oxygen species. The importance of peroxisomal metabolism is illustrated by severe peroxisome biogenesis disorders in which functional peroxisomes are absent or disorders caused by single peroxisomal enzyme deficiencies. These multisystemic diseases manifest specific clinical and biochemical disturbances that originate from the affected peroxisomal pathways. An emerging role of the peroxisome has been identified in many types of diseases, including cancer, neurodegenerative disorders, aging, obesity, and diabetes. Peroxisome homeostasis is achieved via a tightly regulated interplay between peroxisome biogenesis and degradation via selective autophagy, which is commonly known as “pexophagy”. Dysregulation of either peroxisome biogenesis or pexophagy may be detrimental to the health of cells and contribute to the pathophysiology of these diseases. Autophagy is an evolutionary conserved catabolic process for non-selective degradation of macromolecules and organelles in response to various stressors. In selective autophagy, specific cargo-recognizing receptors connect the cargo to the core autophagic machinery, and additional posttranslational modifications such as ubiquitination and phosphorylation regulate this process. Several stress conditions have been shown to stimulate pexophagy and decrease peroxisome abundance. However, our understanding of the mechanisms that particularly regulate mammalian pexophagy has been limited. In recent years considerable progress has been made uncovering signaling pathways, autophagy receptors and adaptors as well as posttranslational modifications involved in pexophagy. In this review, which is published back-to-back with a peroxisome review by Islinger et al. [(Histochem Cell Biol 137:547–574, 2018). The peroxisome: an update on mysteries 2.0], we focus on recent novel findings on the underlying molecular mechanisms of pexophagy in yeast and mammalian cells and highlight concerns and gaps in our knowledge.