Core tip: Mesenchymal stromal cells (MSCs) release immunomodulatory mediators upon inflammatory stimuli. This behavior is attractive for the development of advanced therapeutic strategies applied to several intestinal disorders where inflammation is a key pathophysiological feature. In order to assess quality, efficacy and safety of MSC-based therapy, a novel approach to pharmacokinetics/pharmacodynamics (PK/PD) is mandatory. This must rely on careful assessment of cell phenotype, signaling and homing mechanisms. In this regard, experimental models must take advantage of the most updated knowledge in order to reflect the PK/PD mechanisms in humans. Finally, an alternative approach to the “whole-cell treatment” applies MSC-derived mediators alone in order to avoid the hypothesized serious adverse events deriving from a biological entity mostly acting systemically.