In the last few years, scientists have focused their attention on adult stem cells. It has long been known that stem cells are capable of renewing themselves and can generate multiple cell types. Today, it is demonstrated that stem cells are present in far more tissues and organs than once thought and that they are capable of developing into more kinds of cells than previously imagined. Adult human mesenchymal stromal cells (h-MSC) are prime candidates for many cell-based tissue-engineering applications thanks to their plasticity and easy accessibility. Despite such potential, their use in therapeutic application is still restricted because there are some open issues, which need to be deeply investigated. In this review, we focus on endothelial differentiation of h-MSCs. We comment on some controversies and show how these might arise from h-MSCs heterogeneity and morpho-functional variability. Finally, we highlight the role of extracellular mechanical cues and report on the mechanotransduction pathways activated by micro-/nanotopographies as promising alternative differentiation inducers.