A diversity of pathogens threaten human health. These pathogens include eukaryotes, prokaryotes, and viruses, together encompassing significant variation in their biology. Some have newly emerged in humans, like the RNA virus SARS-CoV-2, while others, like the protozoan parasite Plasmodium falciparum, have circulated in humans for thousands of years. Despite their differences, a common theme among successful pathogens is an ability to evolve to evade our immune responses and control efforts. With the revolution of nucleic acid sequencing over the past 20 years, pathogen genomics can now track evolution in real-time. Genomic methods allow us to determine if pathogen genetic diversity is a benign product of mutation and population dynamics, or if it represents adaptation of the pathogen to better survive. We can further quantify the impact of genetic diversity on disease severity and immune escape by combining sequence data with clinical metadata. In this thesis, I first describe my research using viral genomes and clinical records in Washington State to identify increased SARS-CoV-2 viral loads with the spike D614G mutation, but no alteration in disease severity. 614G was the first amino acid mutation to occur in spike, the receptor-binding protein which mediates entry into cells and is the primary target of protective immunity. At that time in the SARS-CoV-2 pandemic, we did not know if SARS-CoV-2 would evolve to increase its transmissibility, and this work was an early contribution to our understanding of SARS-CoV-2 evolution. This thesis also describes later work using SARS-CoV-2 genomes from Washington State and millions from around the globe to identify positive selection for a different mutation: ORF8 knockout. Much of SARS-CoV-2 genomic surveillance is focused on single nucleotide substitutions in spike, but this work showed how mutations, including deletions, in other parts of the genome can alter pathogen fitness. I also identify decreased hospitalizations and deaths associated with this mutation, illustrating the diverse impact of pathogen evolution on disease severity. The final section of this thesis describes my work using sequence data to understand the impact of previously evolved genetic diversity in P. falciparum on malaria outcomes. Specifically, I aim to use sequencing to understand how the genetic breadth of P. falciparum antigens impacts the development of immunity to malaria using longitudinal samples from a birth cohort in Uganda. I find limited evidence of improved disease outcomes with increasing infection number or antigen-specific exposures in the cohort data. However, I use a longitudinal model of P. falciparum that I built to demonstrate that the lack of signal results from sample collection and study design and is not necessarily biologically meaningful. I further use the model to determine how parasite sequencing can be effectively applied to answer key questions in malaria immunity. This thesis, like the pathogens it describes, covers a diversity of topics; in so doing, it demonstrates the power of pathogen genomics across a wide range of settings to understand continual pathogen evolution and its consequences on human health.