Current strategies to modulate protein expression rely on DNA knock out or RNA interference. A novel method — Trim-Away — can directly and rapidly degrade endogenous proteins in mammalian cells, minimizing the risk of phenotype compensation and off-target effects. Trim-Away introduces exogenous TRIM21 (an E3 ubiquitin ligase) and an antibody against the protein of interest into cells via microinjection or electroporation, leading to TRIM21-mediated ubiquitination and degradation by the proteasome. Trim-Away selectively degraded specific proteins in multiple cell types including primary human cells.