Many neurodegenerative diseases have misfolded proteins as a primary occurrence in pathogenesis. A combination of antibody and genetic engineering has emerged as a powerful tool for developing reagents that specifically target the misfolding process itself, and/or abnormal interactions of the misfolded protein species. This review focuses on the selection and testing of intracellular antibody fragments (intrabodies), with a particular focus on Huntington's disease (HD) and Parkinson's disease (PD), both of which show prominent intracellular protein aggregates in affected neurons. The most dramatic advances are in HD, where in vivo efficacy of intrabodies has been demonstrated. Targets in other neurodegenerative disorders, including Alzheimer's disease and prion diseases, are noted more briefly, with an emphasis on the potential for intracellular manipulations. Given the specificity and versatility of antibody-based reagents, the wide range of options for conformational and post-translationally-modified targets, and the recent improvement in gene delivery, this should be a fertile field for 21(st) century pharmacology.