Introduction: The eradication of a human infectious disease is a major challenge and, if achieved, represents a enormous achievement. This article explores the long and difficult journey towards eradication for polio and guinea worm.

Methods: The authors reviewed the programmatic approaches taken in the eradication strategies for these two diseases and the unique socio-political contexts in which these strategies are couched. The epidemiology of the last 15 years is compared and contrasted. The specific challenges for both programs are outlined and some key elements for success are highlighted.

Discussion: The success of these eradication programs is contingent upon many factors. Nothing is assured, and progress remains fragile and vulnerable to setbacks. Security must be ensured in guinea worm transmission areas in Africa and polio transmission areas in Pakistan and Afghanistan. Technical solutions alone cannot guarantee eradication. National leadership and continued international focus and support are necessary, today more than ever. The legacy of success would be extraordinary. It would reverberate to future generations in the same way that the eradication of smallpox does for this generation.