Non-inferiority (NI) trials enable a direct comparison of the relative benefit-to-risk profiles of an experimental intervention and a standard-of-care regimen. When the standard has clinical efficacy of substantial magnitude that is precisely estimated ideally using data from multiple adequate and well-controlled trials, with such estimates being relevant to the setting of the NI trial, then the NI trial can provide the scientific and regulatory evidence required to reliably assess the efficacy of the new intervention. In clinical practice, considerable uncertainty remains regarding when such trials should be conducted, how they should be designed, what standards for quality of trial conduct must be achieved, and how results should be interpreted. Recent examples will be considered to provide important insights and to highlight some of the challenges that remain to be adequately addressed regarding the use of the NI approach for the evaluation of new interventions. 'Imputed placebo' and 'margin'-based approaches to NI trial design will be considered, as well as the risk of 'bio-creep' with repeated NI trials, use of NI trials when determining whether excess safety risks can be ruled out, higher standards regarding quality of study conduct required with NI trials, and the myth that NI trials always require huge sample sizes.