Chaperone therapy was introduced first as a new molecular therapeutic approach to lysosomal diseases. In a recent article, I reviewed the development of chaperone therapy mainly for lysosomal diseases. Then, more data have been collected particularly on non-lysosomal protein misfolding diseases. In this short review, I propose the concept of chaperone therapy to be classified into two different therapeutic approaches, for pH-dependent lysosomal, and pH-independent non-lysosomal protein misfolding diseases. The concept of lysosomal chaperone therapy is well established, but the non-lysosomal chaperone therapy is heterogeneous and to be investigated further for various individual diseases. As a whole, these two-types of new molecular therapeutic approaches will make an impact on the treatment of a wide range of pathological conditions caused by protein misfolding, not necessarily lysosomal but also many non-lysosomal diseases caused by gene mutations, metabolic diseases, malignancy, infectious diseases, and aging. The concept will open a completely new aspect of protein therapy in future.