new additions to the bioorthogonal chemistry compendium can advance biological research by enabling multiplexed analysis of biomolecules in complex systems . here 
 we introduce the quadricyclane ligation , a new bioorthogonal reaction between the highly strained hydrocarbon quadricyclane and ni bis(dithiolene ) reagents . 
 this reaction has a second - order rate constant of 0.25 m1 s1 , on par with fast bioorthogonal reactions of azides , and proceeds readily in aqueous environments . 
 ni bis(dithiolene ) probes selectively labeled quadricyclane - modified bovine serum albumin , even in the presence of cell lysate . 
 we have demonstrated that the quadricyclane ligation is compatible with , and orthogonal to , strain - promoted azide 
 alkyne cycloaddition and oxime ligation chemistries by performing all three reactions in one pot on differentially functionalized protein substrates . 
 the quadricyclane ligation joins a small but growing list of tools for the selective covalent modification of biomolecules .