In metastatic renal cell carcinoma (mRCC), many factors influence clinical decisions, including histology, tumour burden, prognostic factors, comorbidities, and the ability of the patient to tolerate treatment. Progression-free survival (PFS) durations reported from randomized trials of targeted therapies vary considerably, in part because of differences in patient characteristics. For first-line therapy, an estimate of PFS with sunitinib, bevacizumab plus interferon, or sorafenib in a 'general' population is 8-9 months, but each regimen is suitable for different patient categories. For example, sunitinib is suitable for all-prognosis groups, particularly younger, fitter patients; pazopanib for patients with a good or intermediate prognosis; bevacizumab plus interferon for good-prognosis patients or those with indolent disease; and sorafenib for patients at all prognostic risk levels, particularly the elderly and those with comorbidities. Sequential therapy with targeted agents provides significant benefit, and should be considered in all patients who can tolerate such treatment. Level 1 evidence supports sequential use of tyrosine kinase inhibitors, as well as these agents followed by everolimus. We consider how patient characteristics have influenced the results of studies of first-line therapy, and we provide expert opinion on the most appropriate treatment choices for particular patient groups receiving first-line and second-line therapy.