Pneumonia is the leading cause of death amongst HIV positive persons in Uganda and other resource limited countries. Antimicrobial resistance is rising at an alarming rate throughout the world and complicating the treatment of both pneumonia and tuberculosis. Understanding region-specific microbial causes of pneumonia and their drug resistance attributes is critical for developing successful empiric therapeutic algorithms. At present, little is known regarding the microbial causes of pneumonia in HIV positive persons in Sub Saharan Africa and even less about respiratory pathogen resistance in this important demographic. Advancements in genome sequencing offer a new approach to infection surveillance by affording unbiased, culture-independent assessment of bacterial, viral, mycobacterial and fungal pathogens including their genotypic resistance elements. Here, we describe Pneumo-Seq, a next generation sequencing platform that we will deploy for identifying and characterizing the pathogens responsible for pneumonia in an established and well-characterized prospective cohort study of HIV-positive Ugandans.