Every cell in a human body contains thousands, even hundreds of thousands of tiny RNA genes, which lay mostly undiscovered until the year 2000. Some of these 22-24 nucleotide microRNAs are incredibly conserved across millions of years while other are more species specific and evolve quickly within an organism. But what did all these molecules actually do? How many genes do they affect and by how much? We knew from the earliest discovery of a single microRNA in the worm, that the they cause down-regulation of the target protein by bind in a complementary fashion to the RNA of these protein coding genes. This book starts near the beginnings of their discovery and predicts with our software miRanda, that thousands of genes are regulated in a highly combinatorial fashion by these microRNAs in organisms from fly to human. But the mysteries still remain and microRNAs are now found involved in diverse physiological, developmental and disease conditions. This thesis goes on to show that regulation by microRNAs and siRNAs will depend on systems-level properties, as well as characteristics of individual binding sites in target mRNA molecules and suggest the importance of understanding this for small RNA therapeutic development.