Hereditary inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an increasingly recognized disorder caused by mutations in the Valosin Containing Protein (VCP)/ p97, an ubiquitin-dependent ATPase. VCP plays critical roles in ubiquitin proteasome system (UPS) mediated and autophagy associated protein degradation pathways. Varied phenotypes, including amyotrophic lateral sclerosis (ALS), cardiomyopathy, Parkinson's, myotonia, cataracts and anal incompetence are associated. VCP mutations have also been identified in 1-2% of familial ALS.Immunohistochemistry studies implicate abnormal ubiquitin and TDP-43 inclusions and autophagy. In addition, mouse models developed by other researchers and our R155H VCP knock-in heterozygous mouse model demonstrates progressive weakness including muscle, brain and spinal cord pathology with increasing age. Genomic, muscle microarray, and myoblast studies in this important disorder has also enabled further understanding of the molecular pathophysiology involved in related disorders such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's, Huntington's, and other diseases. Such a comprehensive understanding could lead to novel therapeutic targets. © 2012 by Nova Science Publishers, Inc. All rights reserved.