We report the structures of the terpene cyclases Santalum album L. sesquisabinene synthases 1 and 2 and of santalene synthase, in apo forms, and with the sesquisabinene synthases, bound to either farnesyl diphosphate (FPP), farnesyl S-thiolo-diphosphate, FPP containing a POP bridging O-to-CCl2 substitution, or to sabinene, leading to a sequential mechanism for substrate binding and catalysis. We trapped early pre-catalytic inactive open forms that show how ligands initially bind to the apo-proteins, then when the pocket closes, catalysis can proceed. We also show that there are strong structural similarities between the most highly conserved residues in class I cyclases and those in head-to-tail (aHT) trans-prenyl transferases—outside the well-known DDXXD-like and NSE/DTE-like domains. In the aHT prenyltransferases there is a highly conserved Thr>Gln>Asp>Tyr motif and in the cyclases, a similar Thr>Arg>Asp>Tyr domain, these residues forming very similar, extended H-bond networks (rmsd ~1.4 Å) that are involved in catalysis, leading to the proposal that there are 3 key domains in both the cyclases and the aHT prenyltransferases: The AC-domain that binds MgA and MgC; the B domain that binds MgB and leads to pocket closure, ionization, and condensation or cyclization; and the D-domain H-bond network, involved in H+ elimination. In aHH prenyltransferases the overall folds and MgABC motifs are similar to those found in the cyclase and aHT proteins, but the full Thr>Arg/Gln>Asp>Tyr domain is absent and instead there are Tyr/Asp or Tyr/Glu residues that bind to MgC and are highly conserved. Overall, the results are of general interest since they show unexpected similarities between the enzymes that produce the most diverse molecules on Earth: aHT and aHH prenyltransferases, and terpenoid cyclases.