Membrane desalination that enables the harvesting of purified water from unconventional sources such as seawater, brackish groundwater, and wastewater has become indispensable to ensure sustainable freshwater supply in the context of a changing climate. However, the efficiency of membrane desalination is greatly constrained by organic fouling and mineral scaling. Although extensive studies have focused on understanding membrane fouling or scaling separately, organic foulants commonly coexist with inorganic scalants in the feedwaters of membrane desalination. Compared to individual fouling or scaling, combined fouling and scaling often exhibits different behaviors and is governed by foulant−scalant interactions, resembling more complex but practical scenarios than using feedwaters containing only organic foulants or inorganic scalants. In this critical review, we first summarize the performance of membrane desalination under combined fouling and scaling, involving mineral scales formed via both crystallization and polymerization. We then provide the state-of-the-art knowledge and characterization techniques pertaining to the molecular interactions between organic foulants and inorganic scalants, which alter the kinetics and thermodynamics of mineral nucleation as well as the deposition of mineral scales onto membrane surfaces. We further review the current efforts of mitigating combined fouling and scaling via membrane materials development and pretreatment. Finally, we provide prospects for future research needs that guide the design of more effective control strategies for combined fouling and scaling to improve the efficiency and resilience of membrane desalination for the treatment of feedwaters with complex compositions.