TAR DNA‐binding protein 43 (TDP‐43) is an RNA/DNA‐binding protein involved in RNA regulation and diseases. In 2006, TDP‐43 inclusions were found in the disease lesions of several neurodegenerative diseases. It is the pathological hallmark in both amyotrophic lateral sclerosis and frontotemporal lobar dementia. It also presents in a large portion of patients with Alzheimer's disease. TDP‐43 is prone to aggregate; however, the role of TDP‐43 oligomers remains poorly understood in both physiological and pathological conditions. In this review, we emphasize the role of oligomeric TDP‐43 in both physiological and pathological conditions and discuss the potential mechanisms of oligomer formation. Finally, we suggest therapeutic strategies against the TDP‐43 oligomers in neurodegenerative diseases.