The accumulation of misfolded proteins is associated with numerous degenerative conditions, cancers and genetic diseases. These pathological imbalances in protein homeostasis (termed proteostasis), result from the improper triage and disposal of damaged and defective proteins from the cell. The ubiquitin-proteasome system is a key pathway for the molecular control of misfolded cytosolic proteins, co-opting a cascade of ubiquitin ligases to direct terminally damaged proteins to the proteasome via modification with chains of the small protein, ubiquitin. Despite the evidence for ubiquitination in this critical pathway, the precise complement of ubiquitin ligases and deubiquitinases that modulate this process remains under investigation. Whilst chaperones act as the first line of defence against protein misfolding, the ubiquitination machinery has a pivotal role in targeting terminally defunct cytosolic proteins for destruction. Recent work points to a complex assemblage of chaperones, ubiquitination machinery and subcellular quarantine as components of the cellular arsenal against proteinopathies. In this review, we examine the contribution of these pathways and cellular compartments to the maintenance of the cytosolic proteome. Here we will particularly focus on the ubiquitin code and the critical enzymes which regulate misfolded proteins in the cytosol, the molecular point of origin for many neurodegenerative and genetic diseases.