More research effort needs to be invested in antimicrobial drug development to address the increasing threat of multidrug-resistant organisms. The enzyme DHPS has been a validated drug target for over 70 years as the target for the highly successful sulfa drugs. The use of sulfa drugs has been compromised by the widespread presence of resistant organisms and the adverse side effects associated with their use. Despite the large amount of structural information available for DHPS, few recent publications address the possibility of using this knowledge for novel drug design. This article reviews the relevant papers and patents that report promising new small-molecule inhibitors of DHPS, and discuss these data in light of new insights into the DHPS catalytic mechanism and recently determined crystal structures of DHPS bound to potent small-molecule inhibitors. This new functional understanding confirms that DHPS deserves further consideration as an antimicrobial drug target.