TDP-43 undergoes pathological liquid-liquid phase separation in ALS/FTD, and small molecules that restore liquid-like properties could theoretically address both nuclear loss-of-function and cytoplasmic gain-of-function toxicity. However, this hypothesis faces fundamental barriers: no defined binding pocket exists for intrinsically disordered regions, distinguishing pathological from physiological LLPS remains unsolved, and no validated biomarker exists for target engagement. Precedent failure of aggregation-targeting strategies (tau inhibitors in AD) suggests this approach may not translate.