The increased usage of non-inferiority trials to support regulatory review of new interventions is a relatively recent event in clinical trials history. This talk will cover some of the reasons why clinicians are challenged to understand the principles of understanding NI trials. These issues include confusion about the naming of such trials, the basic reasoning involved in doing NI trials, the ethics of NI trials, biases inherent in their design, what conclusions can be drawn from NI trials, confusion on issues related to study design and issues related to prior evidence of the effects of interventions to support an NI hypothesis with adequate assay sensitivity.