There are over 170 different modifications of nucleotides in RNA, some important for the function or stability of rRNAs, tRNAs, snRNAs and snoRNAs. Modifications also modulate RNA structure-function relationships to control chromatin organization, stem cell differentiation, development, brain function, stress responses, mRNA half-life and miRNA processing, among others. RNA modifications allow mRNA vaccines to evade the innate immune response. RNA is also ‘edited’ by cytosine and adenosine deamination, to form uracil and inosine, respectively. Adenosine editing has expanded in vertebrate, mammalian, and primate evolution, especially in the brain, and in humans occurs largely in Alu elements, which comprise over 10% of the genome. The APOBEC enzymes that deaminate cytosine are vertebrate-specific, the first involved in somatic rearrangement and hypermutation of immunoglobulin domains, and have expanded under positive selection during mammalian and primate evolution, apparently to regulate retroviral and transposable element (TE) activity. TEs are mobilized in the brain, which has many unusual molecular dynamics associated with its ability to re-wire connections. Trans-generational epigenetic inheritance (‘paramutation’) occurs in both plants and animals, and involves small RNA signaling and DNA methylation. Paramutation is associated with simple tandem sequence repeats (STRs), over 1 million of which are present in the human genome and are enriched in enhancers and promoters. STR variation is associated with psychiatric disorders and cancer, as well as the modulation of physiological and neurological traits, suggesting that soft-wired inheritance of experience not only occurs but has been underestimated.