TDP-43 has emerged as a key protein in neurodegenerative diseases. Discovered as a prominent part of protein aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobe dementia (FTLD) postmortem brains, its role in other neurodegenerative pathologies has been revealed. In fact, these discoveries resulted in a new classification of dementia, limbic-predominant age-related TDP-43 encephalopathy (LATE) which shares common symptomatology with Alzheimer’s disease (AD). Here we will review TDP-43 discovery and function, its role in neurodegenerative diseases, and the different in vitro assays to study its role in pathogenesis and to identify compounds able to modulate this key protein in neurodegeneration.