The Humane Society of the United States (HSUS) publicly launched its Pain and Distress Initiative in 2000, to encourage greater attention to the prevention and alleviation of pain and distress in research animals. The initiative's ultimate goal is the phasing out of all significant pain and distress in animal research by 2020. There have been several developments to date. A survey conducted for The HSUS revealed that Americans strongly oppose the use of animals in experiments that cause them to suffer. The HSUS has begun producing a newsletter, The Pain & Distress Report, distributed periodically to over 2000 Institutional Animal Care and Use Committees, scientists and regulators. In 2000, the US Department of Agriculture issued a proposal to upgrade the regulation and reporting of pain and distress. We have challenged the leading research institutions over their under-reporting of unrelieved pain and distress in animals. We have written a comprehensive critique of CO2 euthanasia, arguing that it causes avoidable pain and distress in animals. The National Institutes of Health has issued new guidance on CO2 euthanasia. These developments lay the groundwork for a sustained effort to eliminate animal suffering in research.