Parasitic nematodes pose a significant threat to human and animal health, causing widespread morbidity and substantial socioeconomic losses globally. Despite the utility of anthelmintic drugs in parasite control, the emergence of widespread resistance necessitates the discovery of novel interventions. Advances through the use of whole-organism phenotypic screening have identified some promising nematocidal compounds, including nemacol, tolfenpyrad, UMW-9729, and ABX464. This article summarises efforts in this discovery, with a focus on and as model nematodes, and discusses approaches used for drug target deconvolution, including proteomic, chemical and genetic/genomic techniques. Stability-based proteomic assays, such as thermal proteome profiling, have been useful for identifying protein targets for these compounds, shedding light on their mechanisms of action. However, challenges remain in extrapolating findings from to parasitic nematodes, emphasising the need for validation studies. Understanding drug-target interactions in nematodes is critical for developing next-generation anthelmintics and for mitigating the growing resistance challenge. This review outlines recent progress in this area and discusses future directions in target validation and anthelmintic development to support parasite control programmes.