The objective of this review was to update the relationship between physical activity (PA) and health-related quality of life (HRQL). A systematical search was performed in MEDLINE and PsychINFO between 2000 and 2007, for HRQL- and PA-related keywords in titles, abstracts, or indexing fields. From over 600 retrieved references, 35 citations were judged to require further evaluation. Finally, 10 studies were retained for data extraction and analysis; five were cross-sectional studies, four were cohort and randomized-controlled trails (RCT) studies, and one used a combined cross-sectional and longitudinal design. Cross-sectional studies showed a consistently positive association between self-reported PA and HRQL. The largest cross-sectional study reported an adjusted odds ratio of “having 14 or more unhealthy days” during the previous month to be 0.40 (95% confidence interval 0.36-0.45) for those meeting recommended levels of PA compared with inactive subjects. Cohort studies and RCT tended to show a positive effect of PA on HRQL, but similar to the cross-sectional studies, had methodological limitations. Cross-sectional data showed a consistently positive association between PA level and HRQL. Limited evidence from RCT and cohort studies precludes a definitive statement about the nature of this association.