miRNA strand selection is the process that determines which of the two strands in a miRNA duplex becomes the active strand that is incorporated into the RISC (RNA-induced silencing complex) (named the guide strand, leading strand or miR) and which one gets degraded (the passenger strand or miR). Thermodynamic features of the duplex appear to play an important role in this decision; the strand with the weakest binding at its 5’-end is more likely to become the guide strand. Other key characteristics of human miRNA guide strands are a U-bias at the 5’-end and an excess of purines, whereas the passenger strands have a C-bias at the 5’-end and an excess of pyrimidines. Several proteins are known to play a role in strand selection [Ago (Argonaute), DICER, TRBP (trans-activation response RNA-binding protein), PACT (protein activator of dsRNA-dependent protein kinase) and Xrn-1⁄2]; however, the mechanisms by which these proteins act are largely unknown. For several miRNAs the miR/miR ratio varies dependent on cell type, developmental stage and in different disease states, suggesting that strand selection is a tightly controlled process. The present review discusses our current knowledge regarding the factors and processes involved in strand selection and the many questions that still remain.