RNAi is a conserved gene-specific regulatory mechanism, which silences target gene expression transcriptionally and post-transcriptionally. The RNAi machinery converts the sequence specific information of a long double stranded RNAs (dsRNAs) into small 21-22 nt long dsRNAs (siRNAs, miRNAs) which assemble into an effector complex, the RNA induced silencing complex (RISC). RISC assembly is asymmetric; one strand of an siRNA or a miRNA preferentially incorporates into the RNA-protein complex. Here, I review the rules of the asymmetric RISC formation and discuss their possible regulatory function in several steps in RNAi.