Viruses are obligate intracellular pathogens that must enter and hijack host cells to survive. Many are human pathogens and pose a direct threat to human health worldwide, as seen with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, viral diagnoses are slow, mostly made by ruling out bacterial infections, and treatment methods consists mainly of symptom management. By applying next-generation sequencing (NGS) techniques to virology, we hope to better comprehend how viral infections occur, thereby elucidating new therapeutic targets, as well to diagnose, track, and trace emerging viral variants to guide public health policies. Here, we describe the application of sequencing techniques to two different viruses: lymphocytic choriomeningitis virus (LCMV) and SARS-CoV-2.We begin with a whole-genome functional screen to identify the host repertoire involved in LCMV infection in chapter 2. This high-throughput technique allowed us to rapidly identify known and novel host factors, including sialomucin CD164. We followed up on this protein to highlight its critical role in LCMV entry and speculate on its role in congenital infections. We then developed the foundations necessary for a novel screening modality to elucidate the host factors involved in viral assembly and budding (chapter 3). By combining droplet-based microfluidics and whole-genome screening techniques, we demonstrate the modules necessary for exploring this previously understudied stage of the viral life cycle. The contents of chapters 3 through 7 describes the collaborative work completed during the early days of the SARS-CoV-2 global pandemic with community leaders and UCSF clinicians through the Unidos en Salud (UeS) organization. Prior to the establishment of publicly available, accessible, and rapid testing facilities, we evaluated the performance of the Abbott BinaxNOW rapid antigen tests for coronavirus disease 19 (COVID-19) to detect the virus among symptomatic and asymptomatic individuals by comparing the results of the rapid antigen test with that of a reverse-transcription polymerase chain reaction (RT-PCR) test (Chapter 4). As the pandemic persisted, emerging variants of SARS-CoV-2 were identified by viral genome sequencing technologies. Within our local community, we identified a novel “West Coast” variant, now known as B.1.427 and B.1.429 or the epsilon variant (Chapter 5). Variant distributions combined the extensive metadata collected by UeS revealed an increase in relative household attack rates consistent with a modest transmissibility increase of the epsilon variant. As vaccines and boosters became publicly available, novel variants of concern (VOC) also emerged. In chapter 6, we quantified the efficacy of mRNA vaccines and prior exposures against circulating VOC using an antibody neutralization assay. While vaccines prevented severe disease effectively, post-vaccination breakthrough COVID-19 infections remain a public health concern. We present a detailed case study describing the transmission of the gamma variant (P.1) within an immunized family over the course of several weeks. This characterization revealed not only the complexity of transmission dynamics, but also the necessity of understanding relevant co-morbidities, including auto-immunity to type-1 interferon (Chapter 7). Finally, in chapter 8, we return to our engineering roots and describe an instrument development project, where we designed and assembled a low-cost syringe pump customized specifically to automate production of translationally active cell lysates.