It appears that the genetic programming of humans and other complex organisms has been misunderstood for the past 50 years, because of the assumption that most genetic information is transacted by proteins. However, the human genome contains only about 20,000 protein-coding genes, similar in number and with largely orthologous functions as those in nematodes that have only 1000 cells. On the other hand, the extent of non-proteincoding DNA increases with increasing complexity, reaching 98.8% in humans. The majority of these sequences are dynamically transcribed, mainly into long and short non-protein-coding RNAs, of which there are tens if not hundreds of thousands that show specific expression patterns and subcellular locations. These include not only miRNAs, but also new classes of small RNAs derived from transcription initiation sites and splice sites, and unexpected new classes of long ncRNAs derived from post-transcriptional processing of mRNAs. The emerging evidence indicates that these RNAs form a massive hidden network of regulatory information to control gene expression at various levels, including the site-specificity of the chromatin-modifying complexes that underpin developmental trajectories and cognitive function, and that these regulatory RNAs are dysregulated in cancer and other complex diseases. It is also becoming evident that animals, particularly primates, have superimposed plasticity on these RNA regulatory systems via RNA editing, and that this is the molecular basis of the environment-epigenome interactions that underpin brain function and complex diseases. Retrotransposons also appear to contribute to genomic, epigenomic and transcriptomic plasticity and somatic mosaicism, especially in the brain. Thus, it appears that most assumptions about the nature and structure of regulatory information have been incorrect, and that what was dismissed as ‘‘junk’’ because it was not understood will hold the key to understanding human evolution, development, diversity and cognitive capacity, with revolutionary implications for science, medicine and biotechnology.