Abstract The advent of bioorthogonal chemistry, more importantly the strain‐promoted 1,3‐dipolar cycloaddition of cyclooctynes with azides to give stable triazoles, has opened new avenues for the study of biomolecules in their native environment. While much effort has been focused on improving the kinetics of these reactions, very little attention has been given to their bioselectivity. In this review, we will take you on our journey that led us to develop new cyclooctyne probes with enhanced physical attributes, including water solubility, cell‐surface labeling selectivity and fluorogenic capabilities. We then went on to expand the bioorthogonal chemistry toolbox by focusing on the development of new chemical reporters. Here you will read about our work investigating the use of other 1,3‐dipoles, including nitrile oxides and diazo reagents, for the labeling of biomolecules, and more recently highly biostable sydnones that can be exploited to selectively influence glycan‐processing enzymes.