Due to their anti-inflammatory, antiapoptotic, antimicrobial, and antifibrotic properties, mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of respiratory diseases. Nevertheless, even though MSC administration has been demonstrated to be safe in clinical trials, to date, few studies have shown evidence of MSC efficacy in respiratory diseases. The present review describes strategies to enhance the beneficial effects of MSCs, including preconditioning (under hypoxia, oxidative stress, heat shock, serum deprivation, and exposure to inflammatory biological samples) and genetic manipulation. These strategies can variably promote increases in MSC survival rates, by inducing expression of cytoprotective genes, as well as increase MSC potency by improving secretion of reparative factors. Furthermore, these strategies have been demonstrated to enhance the beneficial effects of MSCs in preclinical lung disease models. However, there is still a long way to go before such strategies can be translated from bench to bedside.