As opposed to organism-based drug screening approaches, protein-based strategies have the distinct advantage of providing insights into the molecular mechanisms of chemical effectors and thus afford a precise targeting. Capitalising on the increasing number of genome and transcriptome datasets, novel targets in pathogens for therapeutic intervention can be identified in a more rational manner when compared with conventional organism-based methodologies. Trehalose-6-phosphate phosphatases (TPPs) are structurally and functionally conserved enzymes of the trehalose biosynthesis pathway which play a critical role for pathogen survival, in particular, in parasites. The absence of these enzymes and trehalose biosynthesis from mammalian hosts has recently given rise to increasing interest in TPPs as novel therapeutic targets for drugs and vaccines. Here, we summarise some key aspects of the current state of research towards novel therapeutics targeting, in particular, nematode TPPs.