Although giardiasis is considered by most medical practitioners to be an easily treated infection, prolonged symptoms due to, or following, Giardia duodenalis infection can have a significant impact on quality of life. Symptom recurrence, including abdominal symptoms and fatigue, can result from re-infection, treatment failure, disturbances in the gut mucosa or post-infection syndromes. In developed countries, these sequelae can have an enormous impact on quality of life; in developing countries, particularly in children, they add yet another burden to populations that are already disadvantaged. Here, we outline current knowledge, based on individual case sequelae from sporadic infections, observations of population effects following outbreaks and studies of phenotypic and genotypic diversity between morphologically identical isolates of parasites. We also raise further questions, looking for clues as to why giardiasis sometimes becomes an intrusive, long-term problem.