MicroRNAs (miRNAs) are a family of small regulatory RNAs whose function is to regulate the activity and stability of specific messenger RNA targets through posttranscriptional regulatory mechanisms. Most of the times signaling systems involving miRNA modulation are not linear pathways in which a certain transcription factor activate the expression of miRNAs that posttranscriptionally represses targeting proteins, but complex regulatory structures involving a variety of feedback-loop architectures.In this book chapter, we define, discuss, and apply a Systems Biology approach to investigate dynamical features of miRNA regulation, based on the integration of experimental evidences, hypotheses, and quantitative data through mathematical modeling. We further illustrate the approach using as case study the signaling module composed by the proteins p53, Sirt1, and the regulatory miRNA miR-34a. The model was used not only to investigate different possible designs of the silencing mechanism exerted by miR-34a on Sirt1 but also to simulate the dynamics of the system under conditions of (pathological) deregulation of its compounds.