The achievement and maintenance of a protein native conformation is a very complex cellular process involving a multitude of key factors whose contribution to a successful folding remains to be elucidated. On top of this, it is known that correct folding is crucial for proteins to play their normal role and, consequently, for the maintenance of cellular homeostasis or proteostasis. If the folding process is affected, the protein is unable to achieve its native conformation, compromising its life and function, and a pathological condition may arise. Protein-misfolding diseases are characterized by either formation of protein aggregates that are toxic to the cell (gain-of-toxic-function diseases) or by an incorrect processing of proteins, which leads to a deficiency in protein activity (loss-of-function diseases). In this article we have focused on proteomics advances in the molecular knowledge of protein-misfolding diseases with direct impact on possible key players in F508del-CFTR processing and trafficking.