Clinical variants ofTARDBPare associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and other degenerative diseases. The predictedC. elegansortholog ofTARDBPis encoded bytdp-1, but functional orthology has not been demonstratedin vivo.We undertook CRISPR/Cas9-based genome editing of thetdp-1locus to create a complete loss of function allele; alltdp-1exons and introns were deleted, creatingtdp-1(tgx58), which resulted in neurodegeneration after oxidative stress. Next, we undertook CRISPR-based genome editing to replacetdp-1exons with human TARDBP coding sequences, creating humanized (hTARDBP)C. elegansexpressing TDP-43.Based on the efficiency of this genome editing, we suggest that iterative genome editing of thetdp-1target locus using linked coCRISPR markers, likedpy-10, would be a more efficient strategy for sequential assembly of the large engineered transgenes.hTARDBPdecreased the neurodegeneration defect oftdp-1(tgx58), demonstrating functional cross-species orthology. To developC. elegansmodels of FTD and ALS, we inserted five different patientTARDBPvariants in theC. eleganshTARDBPlocus. Only one clinical variant increased stress-induced neurodegeneration; other variants caused inconsistent or negligible defects under these conditions. Combined, this work yielded an unambiguous null allele fortdp-1, a validated, humanizedhTARDBP,and multiple ALS/FTD patient-associated variant models that can be used for future studies.