Growing global water challenges, including increasing water shortages and complex wastewater management demands, have driven the development of advanced treatment technologies such as vacuum membrane distillation (VMD). Theoretically, VMD, with its 100% non-volatile contaminant rejection rate and low conductive heat loss, exhibits great potential for high-quality water reuse applications and resource recovery, yet several critical factors determine its viability in real-world implementations. This work explores key variables affecting VMD commercial implementation, including energy requirements and efficiency, membrane fouling and wetting, and water production costs. While recent developments demonstrate promising performance: permeate flux of 10–40 kg/m2h and gained output ratio (GOR) improvements from 0.5 to potentially around 3 through latent heat recovery and renewable energy integration, our analysis reveals that these factors are fundamentally interdependent and cannot be optimised in isolation. Elevated feed temperatures and higher flow rates that enhance water production simultaneously accelerate membrane fouling, wetting, and energy consumption. Mitigation strategies, including hybrid systems for energy recovery and novel membrane materials for fouling resistance, increase capital costs substantially. Water production costs remain significantly higher than mature technologies, ranging from $5–16/m3 compared to <$1/m3 for reverse osmosis. Furthermore, there is a lack of a systematic and comprehensive framework for evaluating VMD system performance holistically. Recent pilot-scale studies indicate VMD’s growing viability, particularly for high-salinity brines, off-grid locations with renewable energy access, and resource recovery scenarios. However, research addressing these interdependencies through integrated optimisation of operating parameters, membrane characteristics, and system design remains essential for VMD’s transition from laboratory-scale to practical, long-term reuse applications.