The contamination of groundwater by arsenic in Bangladesh is a major public health concern affecting 35–75 million people. Although it is evident that high levels (> 300 μg/L) of arsenic exposure from drinking water are related to adverse health outcomes, health effects of arsenic exposure at low-to-moderate levels (10–300 μg/L) are not well understood. We established the Health Effects of Arsenic Longitudinal Study (HEALS) with more than 20,000 men and women in Araihazar, Bangladesh, to prospectively investigate the health effects of arsenic predominately at low-to-moderate levels (0.1 to 864 μg/L, mean 99 μg/L) of arsenic exposure. Findings to date suggest adverse effects of low-to-moderate levels of arsenic exposure on the risk of pre-malignant skin lesions, high blood pressure, neurological dysfunctions, and all-cause and chronic disease mortality. In addition, the data also indicate that the risk of skin lesion due to arsenic exposure is modifiable by nutritional factors, such as folate and selenium status, lifestyle factors, including cigarette smoking and body mass index, and genetic polymorphisms in genes related to arsenic metabolism. The analyses of biomarkers for respiratory and cardiovascular functions support that there may be adverse effects of arsenic on these outcomes and call for confirmation in large studies. A unique strength of the HEALS is the availability of outcome data collected prospectively and data on detailed individual-level arsenic exposure estimated using water, blood and repeated urine samples. Future prospective analyses of clinical endpoints and related host susceptibility will enhance our knowledge on the health effects of low-to-moderate levels of arsenic exposure, elucidate disease mechanisms, and give directions for prevention.