Multipotent mesenchymal stromal cells (MSCs) have unique immunoregulatory and regenerative properties that make them an attractive tool for the cellular treatment of autoimmunity and inflammation. Their underlying molecular mechanisms of action together with their clinical benefit — for example, in autoimmunity — are being revealed by an increasing number of clinical trials and preclinical studies of MSCs. However, autoimmunity and therapy-related alloimmunity are not only triggered and sustained by responses of the adaptive immune system; there is growing evidence that components of the innate immune system also have a key role. It is therefore important to study the crosstalk between MSCs and innate immunity, which ranges from the bone marrow niche to injured tissue.