Background: This article presents lessons learned from an investigation of the acute human health effects of the "Tasman Spirit" oil spill from a perspective of conducting rapid response investigations in developing countries. Methods: We reviewed various steps in our investigation, other studies on oil spills in Pakistan and around the world, and reflected upon our discussions and interactions with various stakeholders. Results: The article highlights the importance of applying a public health, legal, and ethical framework for conducting rapid response investigations, developing a pre-established funding mechanism, and addressing study design issues, exposure and outcome measurements, political issues, community engagement, and communication of results. Conclusion: There is need to develop ethical and legal framework and funding mechanism for conducting rapid response research in developing countries. A repository of study protocols, validated tools, and laboratory methods for exposure and outcome assessment would be greatly beneficial. © 2012 Wiley Periodicals, Inc.