Type 4 cAMP-specific phosphodiesterase (PDE4) is a promising therapeutic target for asthma, but the development of PDE4 inhibitors has been hindered by the side effect of emesis. To improve the therapeutic window of PDE4 inhibitors and identify the specific targets for emesis and efficacy, we prepared an emetic, efficacious, and competitive PDE4 inhibitor (23, APIIMQ) capable of covalently tagging its biological targets upon photoactivation. APIIMQ is potent on PDE4A (IC50 0.4 nM), has a very low emetic threshold (0.1 mg/kg, po, in ferrets), and is effective in functional models (inhibiting LPS-induced TNF-R in human whole blood with IC50 2 µM and guinea pig ovalbumin-induced bronchoconstriction with ED50 0.3 mg/kg). The 125I-labeled APIIMQ specifically labels recombinant PDE4 under photolysis conditions, and this labeling is competed by an active-site-directed potent PDE4 inhibitor, demonstrating that APIIMQ is an active-site-directed specific photoprobe. This probe should be very useful for the identification of the respective targets through which PDE4 inhibitors cause emesis and also produce their efficacy.