<div>Thermal desalination of high salinity water resources is crucial for increasing freshwater supply, but efficiency enhancements are badly needed. Nanomaterial enhancements and novel condensation regimes offer enormous potential for improving promising technologies like membrane distillation (MD). In this work, we first examined nanofluids for MD, including the role of nanoscale physics, and model system-level energy efficiency enhancements. Our model included the dominant micro-mixing from Brownian motion in fine particle nanofluids (copper oxide) and the unusually high axial conduction from phonon resonance through Van der Waals interaction in carbon nanotube nanofluids. Carbon nanotubes resulted in a consistent, wide range of improvements; while copper oxide particles showcased diminishing returns after a concentration of 0.7%, where Brownian motion effects reduced. However, the enhancements at higher concentrations from liquid layering around nanoparticles were impractical in MD, since the related high surfactant levels compromised the membrane hydrophobicity and promoted fouling. Dilute solutions of metallic nanofluids can be actively integrated to enhance the performance of MD, whereas stronger nanofluid solutions should be limited to heat exchangers that supply thermal energy to MD systems. We then investigated slippery liquid infused porous surfaces (SLIPS) for enhanced condensation rates in MD. Dropwise condensation heat transfer was modelled considering the effects of the departing, minimum droplet radii and the interfacial thermal resistances. Effective droplet shedding from these surfaces led to an experimental thermal efficiency of 95%. Alternatively, porous condensers with superior wicking properties and conductive heat transfer offered a robust solution to high salinity desalination. We modelled the onset of flooding in porous condensers using Darcy’s law for porous media, including the effects of the condenser permeability and determined the optimal condenser thickness at varying system length scales. The increased active area of condensation resulted in a significant enhancement (96.5%) in permeate production and 31.7% improvement in experimental thermal efficiency. However, porous condensers were only compatible with flat plate module designs limiting their practicality.</div>