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Systems molecular medicine is the science of combining systems biology with molecular analysis and intervention to address clinically relevant questions. MicroRNAs (miRNAs) appear particularly suitable to serve as hubs of regulatory networks underlying complex diseases. Clear experimental evidence for coordinated regulation of a large number of genes by miRNAs, however, is still rare. It leaves open several fundamental questions that are important for determining the value of miRNA in complex regulatory networks and in systems molecular medicine. Physiological genomics is a powerful approach for addressing these open questions.