In this review, we recapitulate most of the recent advances in search for in vivo detection of TDP-43 proteinopathies for clinical use, classifying the different approaches into four main categories: (1) detection of soluble TDP-43 in biofluids, (2) functional and structural neuroimaging directly or indirectly associated with TDP-43, (3) detection of aberrant TDP-43 in cells and tissues outside the CNS, and (4) indirect detection of TDP-43 loss-of-function splicing by cryptic exon neoepitopes. This evidence concerns the gene TARDBP and proteostasis deficiencies.