While randomized well-controlled clinical trials have been viewed as the gold standard in the evaluation of therapeutic medical products, it is not uncommon for some clinical studies to depart from the paradigm of such randomized trials, due to ethical or practical reasons. In these observational studies, the advantages of well-designed and conducted randomized clinical trials are no longer available, and then the statistical inference obtained may have lower level of scientific assurance. To deal with the limitations of observational studies, there has been an increased interest in applying the propensity score methodology. However, there are many challenges in its application in terms of study design and statistical analysis as well as regulatory issues. In this talk, some statistical and regulatory issues will be discussed and illustrated with examples from a regulatory perspective.