The Aga Khan University’s Health and Demographic Surveillance System (HDSS) in peri urban areas of Karachi was set up in the year 2003 in four low socioeconomic communities and covers an area of 17.6 square kilometres. Its main purpose has been to provide a platform for research projects with the focus on maternal and child health improvement, as well as educational opportunities for trainees. The total population currently under surveillance is 249,128, for which a record of births, deaths, pregnancies and migration events is maintained by two monthly household visits. Verbal autopsies for stillbirths, deaths of children under the age of five years and adult female deaths are conducted. For over a decade, the HDSS has been a platform for a variety of studies including, calculation of the incidence of various infectious diseases like typhoid bacteremia, pneumonia and diarrhea, evaluation of effectiveness of various treatment regimens for neonatal sepsis, assessment of the acceptance of hospitalized care, determination of the etiology of moderate to severe diarrhea, assessment of burden and etiology of neonatal sepsis and a multi-centre cohort study measuring the burden of stillbirths, neonatal and maternal deaths. We have also established a bio-repository of a well-defined maternal and newborn cohort. Through a well-established HDSS rooted in maternal and child health we aim to provide concrete evidence base to guide policy makers to make informed decisions at local, national and international levels.