South Asia despite decreasing rates of infectious disease, accounts for a significant proportion of their global burden. The sub-continent is also in the midst of rapid economic growth; large scale changes in land use, access to water and sanitation, and agricultural production; environmental degradation; and technological transformation, all against a background of uneven health system capacity. South Asia, defined by the World Bank as Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka, is home to a quarter of the world’s population. Existing infectious disease challenges—including tuberculosis, HIV, and malaria—have been augmented by emerging and growing threats such as dengue, chikungunya, healthcare associated infections, and antimicrobial resistance. These emerging and re-emerging infectious disease challenges threaten to create economic disruption and potentially large morbidity and mortality burdens. Here we review the status, vulnerability, and preparedness for emerging and re-emerging infectious diseases and describe the state of preparedness and surveillance for threats such as Zika, Middle East respiratory syndrome coronavirus (MERS-CoV), and avian influenza.