Circulating microRNAs (ci-miRNAs) are secreted from various tissues, including the endothelium, in response to exercise. MiRNAs are transported from the nucleus (details of biogenesis are omitted) into the cytoplasm, where they associate with proteins (Argonaute, miRISC) and are secreted into the bloodstream. Ci-miRNAs may circulate in association with proteins or may additionally be packaged into extracellular vesicles (exosomes or microvesicles), high-density lipoproteins (HDLs) or released in apoptotic bodies. Increased shear stress along the endothelium is one mechanism potentially responsible for the altered ci-miRNA profile observed with exercise, because it may stimulate the secretion of specific miRNAs from endothelial cells. Ci-miRNAs may then be absorbed from the circulation by distant tissues, where they exert their effects by regulating gene expression. MiRNAs most often cause downregulation or inhibition of translation in target cells by inducing translational repression, mRNA degradation, or deadenylation of complementary mRNAs. Ci-mRNAs altered with acute and chronic exercise are proposed to mediate/moderate beneficial adaptations to training through translational downregulation of their target mRNA transcripts. We propose that ci-miRNAs released from the endothelium in response to exercise-induced increases in shear stress may be taken up by endothelial cells in vessels of inactive tissues to facilitate adaptations. For specific details of biogenesis, see (39, 108).