For the past 15 years, the field of amyotrophic lateral sclerosis (ALS) pathophysiology and drug development has largely been dominated by understanding the biology surrounding mutations in superoxide dismutase; the first gene mutation identified in familial ALS. In spite of a large amount of research surrounding the pathobiology of this mutation in animal models and in vitro, no successful human therapy has resulted from the many positive preclinical observations and clinical experiments based on mutant superoxide dismutase 1 (SOD1). The identification of two new familial ALS mutations in the past 2 years has potentially dramatically changed that. The identification of the TAR DNA-binding protein (TDP-43) in ubiquitinated protein aggregates found in many patients with sporadic ALS (but not familial SOD1-mediated ALS) or the most common form of frontotemporal dementia called frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) has raised the possibility that this protein may be either a byproduct or an initiator of sporadic ALS (Lagier-Tourenne et al, 2010). The importance of this purely pathological observation was solidified and intensified when dominant mutations of TDP-43 were found in multiple ALS families and may account for up to 3% of familial ALS cases (Lagier-Tourenne et al, 2010). Perhaps equally significant has been the observation that almost all sporadic ALS post-mortem specimens have TDP-43 aggregates present in neurons and glia. Subsequently mutations in the RNA-metabolizing protein FUS were also found in a small subset of familial ALS patients. Thus, a new mechanism of familial ALS pathophysiology, aberrant RNA metabolism, suggested in sporadic ALS a decade earlier (Lin et al, 1998), appears to be an important ALS initiator. Importantly for the investigation of motor neuron disease, animal models using TDP-43 mutations have been developed, which afford a new model for the study of potential ALS-related drug therapies (Wegorzewska et al, 2009).