Peroxynitrite is a prominent biological reactive nitrogen species from radical combination of nitric oxide and superoxide and fundamentally involved in broad spectrum physiological and pathological processes. Though redox-inert itself, peroxynitrite anion (OONO(-)) attacks various biological electrophiles to generate an array of potent 2-e(-) or 1-e(-) oxidants, which result in cell injuries. Development of fluorescent probes for peroxynitrite, free from interference from hypochlorite, has been an active endeavor of the chemical community. We previously reported a peroxynitrite probe (PN600), which could differentiate hypochlorite from peroxynitrite through a multichannel signaling mechanism. Herein, this intriguing selectivity was accounted for through a structure-reactivity relationship study. Also, this work, together with rich literature contributions, has allowed a qualitative guideline in the use of electron-rich aromatic moieties to design probes against peroxynitrite and/or hypochlorite. The viability of this guideline was further testified by development of another list of peroxynitrite selective probes.