Membrane distillation (MD) has been garnering increasing attention in research and development, since it has been proposed as a promising technology for desalinating hypersaline brine from various industries using low-grade thermal energy. However, depending on the application context, MD faces several important technical challenges that would lead to compromised performance or even process failure. These challenges include pore wetting, mineral scaling, and membrane fouling. This review is devoted to providing a state-of-the-art understanding of fundamental mechanisms and mitigation strategies regarding these three challenges. Guided by the fundamental understanding of each membrane failure mechanism, we discuss both operational and material strategies that can potentially address the three technical challenges. In particular, the material strategies involve the development of MD membranes with tailored special wetting properties to impart resistance against different types of membrane failure. Lastly, we also discuss research needs and best practices in future studies to further enhance our ability to overcome technical challenges toward the practical, sustainable, and scalable applications of MD.