The etiological agents of schistosomiasis are snail-vectored, waterborne, parasitic trematodes of the genus Schistosoma. Schistosomes are considered a considerable public health concern responsible for infecting over 236 million people across 78 endemic nations. It is especially common among children in low and middle-income countries, with 90% of infections occurring in sub-Saharan Africa. As a consequence, they are now targeted by the World Health Organization for control and ultimately elimination through mass-drug administration (MDA), reliant on the only available drug, praziquantel. In this thesis, I first present the results of the first genomic study investigating the potential impact of long-term mass-drug administration (MDA) on Schistosoma mansoni populations, examining these populations from within Uganda with contrasting histories of past drug pressure, and sampling both pre- and post- praziquantel treatment. In particular, I examine how long-term MDA has impacted the population structure of S. mansoni and whether there is evidence of ongoing drug-induced selection that could represent the appearance of praziquantel drug resistance. In the following chapter, I reexamine this dataset along with additional samples from other genomic studies and newly sequenced samples. Using this more extensive dataset I explored population structure over larger spatial scales, identified clear evidence of hybridization with the closely related species S. rodhaini. In-depth sequencing of parasites infrapopulations permitted examination of the changes of infrapopulation relatedness after praziquantel treatment. Finally, I examined variation in a recently identified putative praziquantel resistance conferring gene. I then performed genomic characterization of livestock infective schistosome populations, focusing on the incidence of early generation hybrids between S. bovis and S. curassoni. In the following chapter I present the results of a long-term genome assembly project, aiming to produce genome assemblies and annotations for Schistosoma and other parasitic flatworms. This resulted in 19 chromosomal-scale assemblies for 14 species of parasitic flatworm, with Iso-Seq and RNA-seq based annotations. I then performed a range of comparative genomic analyses aiming to characterize interspecies variation at both the chromosomal and gene family level. The primary aim was to define specific trends in evolution of this genus.