The activity and lifetime of proteins or peptides in living organisms depend on proteolytic enzymes. Proline residues impose conformational constraints, requiring specific proline-specific proteases. Among these, prolyl oligopeptidase (POP, EC 3.4.21.26) is a post-proline-endopeptidase that cleaves peptides on the carboxy side of proline residues in the core of peptide chains. Over the past 2 decades, abnormal mammalian POP activity has been linked to neurological disorders. To better understand and treat these diseases and minimize toxicity and side effects, POP inhibitors must be potent and selective for the target enzyme. This Perspective first highlights the similarities and differences between a few proline-specific proteases. Then, it focuses on POP and discusses the structure-activity relationship of inhibitors developed as potential therapeutic drugs for neurological disorders. Furthermore, it discusses two possible pharmacophores—one encompassing features to achieve selectivity for POP over other proline-specific proteases and another ranking features to improve inhibitor potency. This Perspective focuses on a selection of reports that illustrate the discussion on POP inhibitors and their inhibitory potency and selectivity, covering most key articles and inhibitors representative of the literature and patents as of today (without claiming to be exhaustive). The data collected are believed to guide the future development of novel, selective POP inhibitors as more effective candidate drugs.