There are now five targeted agents, i.e. sorafenib, sunitinib, temsirolimus, bevacizumab (in combination with interferon) and everolimus, that have been shown to improve the outcome in patients with metastatic clear cell renal cell carcinoma (mRCC), in randomized controlled trials (RCTs). Compared with the period when cytokines were the only systemic intervention known to have any activity, decisions on medical management are now complex. Clinicians must seek to adjust therapy to the circumstances of the individual patient, and consider the sequencing of agents. In this context, several expert groups have sought to provide treatment guidelines. As in other diseases, guidelines for mRCC seek to establish evidence-based recommendations for best clinical practice and to encourage their widespread use. Data from phase III trials (level 1 evidence) are an essential element in this process, and guidelines need continual updating in the light of new findings. However, there are inevitably questions that large RCTs have not directly addressed. This is the case for major subgroups of the mRCC population, e.g. the elderly and those with comorbidities. In these circumstances, less well-controlled sources of data, and clinical experience, have a role to play. Certain guidelines (although not all) acknowledge the contribution that such sources of evidence can make.