Until a couple of years ago, TAR-DNA-binding protein-43 (TDP-43) was a relatively unknown nuclear protein implicated in transcriptional repression and splicing. Since 2006, when the protein was reported to be present in inclusions in the neurons and/or glial cells of a range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive, tau- and α-synuclein-negative inclusions (FTLD-U) and Alzheimer's disease (AD), many reports on the medical aspects of TDP-43 have been published. Here, we summarize the current literature on TDP-43, focusing on recent studies that provide clues to the function of TDP-43. Using this information and database analysis, we also suggest a molecular and cellular model for possible events in normal and diseased neurons in relation to the emerging importance of the function and dysfunction of this protein as a target for basic as well as translational research.