Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, EC 3.1.4.1) is a metalloenzyme that belongs to the NPP family, which comprises seven subtypes (NPP1-7). NPP1 hydrolyzes a wide range of phosphodiester bonds, <i>e.g.</i> in nucleoside triphosphates, (cyclic) dinucleotides, and nucleotide sugars yielding nucleoside 5'-monophosphates as products. Its main substrate is ATP which is cleaved to AMP and diphosphate. The enzyme is involved in various biological processes including bone mineralization, soft-tissue calcification, insulin receptor signalling, cancer cell proliferation and immune modulation. Therefore, NPP1 inhibitors have potential as novel drugs, <i>e.g.</i> for (immuno)oncology. In the last two decades several inhibitors of NPP1 derived from nucleotide- or non-nucleotide scaffolds have been developed. The most potent and selective NPP1-inhibitory substrate analog is adenosine 5'-α,β-methylene-γ-thiotriphosphate (<i>K</i><sub>i</sub> = 20 nM <i>vs. p</i>-Nph-5'-TMP, human membrane-bound NPP1). Non-nucleotide-derived NPP1 inhibitors comprise polysulfonates, polysaccharides, polyoxometalates and small heterocyclic compounds. The polyoxometalate [TiW<sub>11</sub>CoO<sub>40</sub>]<sup>8-</sup> (PSB-POM141) is the most potent and selective NPP1 inhibitor described to date (<i>K</i><sub>i</sub> = 1.46 nM <i>vs.</i> ATP, human soluble NPP1); it displays an allosteric mechanism of inhibition and represents a useful pharmacological tool for evaluating the potential of NPP1 as a novel drug target.