Protein homeostasis or “proteostasis” can be defined as the process maintaining a healthy proteome in cells. The proteostasis machinery may act on proteins as soon as they exit the ribosomal tunnel, ensuring that they adopt a correct fold and are targeted to the right cellular location. Subsequent protein assembly into complexes may also be understood as a proteostatic phenomenon, as complexes often protect their components from degradation. Indeed, an increasing number of storage structures such as filaments or membrane-less assemblies have been recently characterized. Lastly, proteins no longer needed or damaged must be degraded by the ubiquitin-proteasome and autophagy pathways. While research has traditionally focused on cytoplasmic proteostatic mechanisms, it is now clear that organelles like the endoplasmic reticulum or mitochondria possess unique machineries to maintain their proteome health. Our proteostasis capacity declines with age, and proteostasis derailment is associated with diseases of brain and heart. A hallmark of the most prevalent neurodegenerative diseases is the aggregation of misfolded proteins, which often adopt amyloid folds. Amyloids can also affect the heart as in e.g. amyloid cardiomyopathy. Beyond misfolding, aberrant quality control of key cardiomyocyte components (e.g. proteolytic processing of junctophilin 2) also has pathological implications. Therefore, therapeutic interventions aimed to restoring the cellular proteostatic capacity hold great promise for both neurological and cardiac disorders.