Selective reactions with proteins carrying unique chemical reporters in cells offer powerful tools to study protein dynamics and function in their native environment. In this talk, I will discuss our work on the development of two bioorthogonal reactions: a photoinducible tetrazole-alkene cycloaddition reaction (“photoclick” chemistry) and a palladium-mediated copper-free Sonogashira cross-coupling reaction; and their uses in selectively labeling proteins in living cells. The optimizations have led to the tetrazoles with tunable photoactivation wavelength including a femtosecond pulsed infrared laser along with robust reaction kinetics, as well as new palladacycles suitable for biological applications. To interface effectively with biology, we have also accomplished the genetic incorporation of the unnatural amino acids carrying these reporters site-selectively into proteins. I will conclude the talk by discussing our recent effort in using phage display to evolve sequence-specific bioorthogonal reactions with superior reaction kinetics and specificity.