Despite decades of progress and a drastic reduction in malaria burden worldwide since the implementation of the Global Malaria Strategy in 1992 and Roll Back Malaria in 1998, malaria incidence rates and deaths in 2020 had their most dramatic increase since the start of the millennium. Plasmodium species exhibit remarkably flexible genomes that allow them to adapt and evolve to any range of selective pressures within their environment, from host immune evasion and the acquisition of protective phenotypes to the development of a wide array of drug resistance mechanisms. The aim of this thesis is to demonstrate the potential application of next-generation sequencing technologies within the field of malaria disease surveillance, as well as present novel information surrounding East African Plasmodium falciparum populations. Despite accounting for 10% of all malaria cases worldwide annually, and the recent emergence of locally spreading clinically artemisinin resistant P. falciparum parasites in Uganda, East African parasite populations have been largely underrepresented in whole genome population studies. To supplement the availability of sequencing data and provide insights into the population structure of P. falciparum parasites in East Africa, I generated the first baseline assessment of malaria parasites from the Kenyan region of Lake Victoria, which identified the presence of unique ancestral origins for Lake Victoria isolates compared to other Kenyan parasite populations, as well as a potential genetic subgroup within the wide East African population. To further investigate the genetic structure of East African P. falciparum parasites, I generated sequencing data for parasites collected along the Kenya-Uganda border and created a genomic dataset using publicly available data from regions across Kenya, Tanzania, and Uganda. This expanded dataset confirmed the presence of subpopulations within the East African parasite population, including a distinct genetic structure amongst isolates from Western Kenya, the Kenyan region of Lake Victoria, and Central Uganda, confirming our initial findings. Although the benefits of implementing WGS-based analyses within this region of high transmission cannot be understated, the cost of sequencing can still be cost prohibitive in low-resource settings, such as those presented within this thesis. I supplemented whole genome sequencing (WGS)-based analyses within this thesis with low-cost dual-indexing (e.g., DNA barcoding) amplicon sequencing to achieve high throughput coverage of not only parasite drug resistance markers, but also human genetic variants associated with malaria disease severity or protection. WGS demonstrates limited efficacy when attempting to sequence sub microscopic or low-density infections due to low levels of available template DNA. Ngodhe island, located within the Kenyan region of Lake Victoria, has a unique malaria transmission profile with asymptomatic and sub-microscopic infections accounting for most cases. To overcome this barrier, I utilised the low-cost targeted sequencing methods to generate a drug resistance profile of P. falciparum parasites from Ngodhe island for the first time. Malaria is a dynamic parasitic infection that will require a multifaceted approach towards control, encompassing not only the parasite and vector-based methods, but also increased insight into the human genetics of malaria infection protection and risk. To demonstrate the versatility of this technology, I presented a proof-of-concept method for profiling the human genetic determinants of malarial disease in an at-risk population in Northeast Tanzania. This thesis presents a multifaceted approach to disease surveillance by using both whole genome sequencing and custom targeted sequencing to characterise the genomic and genetic diversity of P. falciparum populations in high transmission regions of East Africa, as well as the genetic determinants of malarial disease in at-risk human populations.