The use of dermal substitutes is increasingly widespread but the outcomes of substitute-assisted healing remain functionally deficient. Presently, the most successful scaffolds are acellular polymer matrices, prepared through lyophilization and phase separation techniques, designed to mimic the dermal extracellular matrix. The application of scaffolds containing viable cells has proven to be problematic due to short shelf-life, high cost and death of transplanted cells as a result of immune rejection and apoptosis. Recent advances in biomaterial science have made new techniques available capable of increasing scaffold complexity, allowing the creation of 3D microenvironments that actively control cell behaviour. Importantly, it may be possible through these sophisticated novel techniques, including bio-printing and electrospinning, to accurately direct stem cell behaviour. This complex proposal involves the incorporation of cell-matrix, cell-cell, mechanical cues and soluble factors delivered in a spatially and temporally pertinent manner. This requires accurate modelling of three-dimensional stem cell interactions within niche environments to identify key signalling molecules and mechanisms. The application of stem cells within substitutes containing such environments may result in greatly improved transplanted cell viability. Ultimately this may increase cellular organization and complexity of skin substitutes. This review discusses progress made in improving the efficacy of cellular dermal substitutes for the treatment of cutaneous defects and the potential of evolving new technology to improve current results.