In this work, we addressed this gap in chemistry: we elaborated a general practical method for trifluoromethyl and difluoromethyl aliphatic diazirines, characterized them and studied them in model photolabeling and biological experiments (Figure ). Moreover, we have shown that the undeservedly neglected before aliphatic trifluoromethyl diazirines could be safely used as photoaffinity labels, while the difluoromethylating analogues -cannot, due to chemical instability.