It is now established that pathological transactive response DNA‐binding protein with a Mr of 43 kD (TDP‐43) on sodium dodecyl sulfate‐polyacrylamide gel electrophoresis is the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin‐positive inclusions (now known as FTLD‐TDP). In fact, the discovery of pathological TDP‐43 solidified the idea that these disorders are multi‐system diseases and this led to the concept of a TDP‐43 proteinopathy as a spectrum of disorders comprised of different clinical and pathological entities extending from ALS to ALS with cognitive impairment/dementia and FTLD‐TDP without or with motor neuron disease (FTLD‐MND). These align along a broad disease continuum sharing similar pathogenetic mechanisms linked to pathological TDP‐43. We here review salient findings in the development of a concept of TDP‐43 proteinopathy as a novel group of neurodegenerative diseases similar in concept to α‐synucleinopathies and tauopathies.