The stability of the proteome is crucial to the health of the cell, and contributes significantly to the lifespan of the organism. Aging and many age-related diseases have in common the expression of misfolded and damaged proteins. The chronic expression of damaged proteins during disease can have devastating consequences on protein homeostasis (proteostasis), resulting in disruption of numerous biological processes. This chapter discusses our current understanding of the various contributors to protein misfolding, and the mechanisms by which misfolding, and accompanied aggregation/toxicity, is accelerated by stress and aging. Invertebrate models have been instrumental in studying the processes related to aggregation and toxicity of disease-associated proteins and how dysregulation of proteostasis leads to neurodegenerative diseases of aging.