Measurably evolving pathogens present an attractive system to study via sequence analysis. High mutation and recombination rates, strong and diverse selective pressures, and complex intra-host and population level dynamics create information-rich datasets. The ubiquitous use of next generation sequencing platforms for generating high-resolution data sets creates a catch-22 situation: we can fit ever more complex and biologically realistic models because of larger datasets, but these models are increasingly more computationally demanding. I will discuss how we handle the challenge of large volumes of sequencing data in HIV-1 studies which seek to understand how the pathogen interacts with the host immune system (and escapes the action of potent responses), how viral population structure may affect the efforts to develop a functional cure, and how molecular epidemiology is driving modern efforts at driving the HIV-1 epidemic to extinction.