Abstract: This invention pertains to a method of metabolically destabilizing a protein or peptide of interest in vivo provided that the protein or peptide contains a second determinant of the N-end rule-based degradation signal and provided that another (targeting) protein or peptide can be identified that specifically interacts with the protein or peptide of interest. The methods of the invention comprise contacting the protein or peptide of interest with the targeting protein or peptide which contains a destabilizing amino-terminal amino acid according to the N-end rule of protein degradation but lacking a second determinant of the N-end rule-based degradation signal. Because nearly all proteins specifically interact with other proteins, this is a broadly applicable method for metabolically destabilizing a protein or peptide of interest in vivo.