In a time of increasing antibacterial resistance and limited availability of new antibiotics, clinical studies are much needed to assess treatment options against multidrug-resistant organisms (MDROs). In this review, we describe the clinical challenge caused by MDROs and present recent evidence on how clinical studies may generate quality data to improve antibiotic treatment of MDRO infections. To this aim, we critically assess the current status, gaps and challenges associated with observational and interventional studies performed to assess MDRO treatment options. We address why observational studies are useful, which treatment options for MDRO have been explored by observational studies and how to improve quality and usefulness of observational studies. Furthermore, the utility of clinical pharmacokinetic/pharmacodynamic studies for improving MDRO treatment is described. Finally, we discuss interventional study designs, end points and margins, as well as ethical, logistic and statistical challenges, and current regulatory changes proposed to foster the development of new antibiotics.