Comparative effectiveness research (CER) is not new but its potential to improve the effectiveness of healthcare has not yet been exploited in the US. Other countries such as the UK have more experience of this. Key points of the UK experience are summarized here and some possible pointers for the US are drawn. These include the following: how to go beyond the evidence and apply judgements to make recommendations with authority and in a timely manner; how to implement these recommendations; how to identify suitable topics; and how to be open and transparently fair to all stakeholders. The quality of the science of CER is key but this needs developing, and not just in biomedical or statistical terms but also in how to understand public expectations, and how to implement its recommendations. A key issue is the role of health economics, which seems to have been marginalized by the CER legislation, but perhaps this is more apparent than real. Clearly this is a matter for much further debate. It is hard to see how CER can deliver its potential without active consideration of both benefits and costs. Although other countries have more experience of this than does the US, the context for such work is always very specific and the US will have to find its own way, while trying to avoid some of the errors made elsewhere.