Nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) catalyzes the hydrolysis of extracellular nucleotides. It is expressed by immune cells and some carcinomas, <i>e.g.</i> of kidney and colon. Together with ecto-5'-nucleotidase (CD73), NPP3 produces immunosuppressive, cancer-promoting adenosine, and has therefore been proposed as a target for cancer therapy. Here we report on the discovery of 4-[(4-methylphthalazin-1-yl)amino]benzenesulfonamide (<b>1</b>) as an inhibitor of human NPP3 identified by compound library screening. Subsequent structure-activity relationship (SAR) studies led to the potent competitive NPP3 inhibitor 2-methyl-5-{4-[(4-sulfamoylphenyl)amino]phthalazin-1-yl}benzenesulfonamide (<b>23</b>, <i>K</i> <sub>i</sub> 53.7 nM <i>versus</i> the natural substrate ATP). Docking studies predicted its binding pose and interactions. While <b>23</b> displayed high selectivity <i>versus</i> other ecto-nucleotidases, it showed ancillary inhibition of two proposed anti-cancer targets, the carbonic anhydrases CA-II (K<sub>i</sub> 74.7 nM) and CA-IX (K<sub>i</sub> 20.3 nM). Thus, <b>23</b> may act as multi-target anti-cancer drug. SARs for NPP3 were steeper than for CAs leading to the identification of potent dual CA-II/CA-IX (<i>e.g.</i> <b>34</b>) as well as selective CA-IX inhibitors (<i>e.g.</i> <b>31</b>).