MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression in many eukaryotes. miRNAs were first discovered in Caenorhabditis elegans by Victor Ambros' laboratory in 1993. At the same time Gary Ruvkun's laboratory identified the first miRNA target gene. Together, these two seminal discoveries identified a novel mechanism of post-transcriptional gene regulation that has been recognized as important for development, physiology and pathology of many organisms. Here we discuss how functional genomic, computational and proteomic approaches complement classical genetic analyses to unravel miRNA biology in C. elegans.