The homeostasis of the protein synthesis and degradation is crucial for cell survival. Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. The principal routes of intracellular protein metabolism are the ubiquitin proteasome system (UPS) and the autophagy-lysosome pathway (ALP). They collaborate to degrade wasted proteins and interact each other to cope with the pathological conditions, in which molecular chaperones play collective roles by assisting the protein targeting to the proteasome or autophagy. It is known that intracellular protein degradation functions are decreased with aging in many tissues and organs. Failure to perform their functions could underlie the inability of cells to adapt to stress conditions, lead to accelerated course of misfolding protein deposit and the inclusion body formation, and eventually result in neurodegeneration.One of the functions of the molecular chaperones is to help the new synthesized or the misfolding toxic proteins fold to their native and nontoxic formation. In this review, we analyze the recent perceptions and findings of molecular chaperones biology in the two degradation pathways and their pathological attribution in several neurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD), Huntingtons disease (HD), and others. It is worthy noticing that some of the heat shock proteins (HSPs) can not only block the protein aggregation in the early stages, but also have promising effect on attenuating the formation of fibrils. Further more, when the degradation pathways are too weak to degrade all the toxic soluble proteins, molecular chaperones can also help to sequenstrate the toxic proteins into inclusion bodies. Therefore, the study of HSPs might shed new light on not only the mechanisms of protein synthesis and degradaton, but also the possible therapeutic targets of fibril formation associating diseases.