Researchers have used cryo-electron microscopy to take two new snapshots of the spliceosome, the enormous protein and RNA machinery responsible for removing segments of messenger RNA (mRNA) called introns prior to protein production. In addition to its pruning responsibilities, the spliceosome also stitches together remaining sections of mRNA into a cornucopia of combinations so that the ribosome can build an average of 10 unique proteins per gene found in the human genome. This machinery gives humans much more complexity than fruit flies, which possess similar numbers of genes. The new snapshots of the spliceosome, delivered by Yigong Shi and colleagues at Tsinghua University capture the machinery in an activated, presplicing state as well as in a catalytic conformation. Together, the images feature four RNAs and 30-plus proteins, for a combined molecular mass of more than 1 megadalton at a resolution of just more than 3 Å (Science 2016, DOI: 10.1126/science.aag0291 and 10.1126/science.aag2235). Among other insights, the precatalytic structure reveals that the spliceosome recognizes negatively charged intron sequences by means of positively charged surface patches on two proteins in the mega-machinery. The other structure provides insights about the way the megamachinery performs the first of two sequential transesterification reactions.