After encoding by the nuclear genome, all proteins are translated in the cytoplasmic free ribosomes. While some of them remain in the cytosol, others are targeted into the endoplasmic reticulum (ER). Entry into the ER and folding process must be completed correctly and checked by the quality control system in the ER. ER-resident foldases and molecular chaperones are members of the ER protein quality control system. When the activity in the protein folding system exceeds the capacity of the ER and the quantity of the incorrectly folded proteins increases, the incorrectly folded proteins begin to accumulate in the lumen of the ER. This process triggers ER stress and has a major impact on the pathogenesis of several diseases. Three major ER transmembrane stress transducers trigger adaptive gene expression cascade and restoration of the ER homeostasis. Unfolded protein response (UPR) and endoplasmic reticulum stress have a major impact on both physiological developments of cartilage tissue and pathological situations. New treatment methods can be improved by inhibition of ER stress, activation of chaperon-mediated protein folding or increasing endoplasmic reticulum-associated degradation (ERAD).