Sustaining neuronal proteostasis during the course of our life is a central aspect required for brain function. The dynamic nature of synaptic composition and abundance is a requisite to drive cognitive and motor processes involving a tight control of many aspects of protein biosynthesis and degradation. Through the concerted action of specialized stress sensors, the proteostasis network monitors and limits the accumulation of damaged, misfolded, or aggregated proteins. These stress pathways signal to the cytosol and nucleus to reprogram gene expression, enabling adaptive programs to recover cell function. During aging, the activity of the proteostasis network declines, which may increase the risk of accumulating abnormal protein aggregates, a hallmark of most neurodegenerative diseases. Here, I discuss emerging concepts illustrating the functional significance of adaptive signaling pathways to normal brain physiology and their contribution to age-related disorders. Pharmacological and gene therapy strategies to intervene and boost proteostasis are expected to extend brain healthspan and ameliorate disease states.