Telomerase extends chromosome ends by iterative reverse transcription of its RNA template. Following the addition of each telomeric repeat, the RNA template and the telomeric substrate reset their relative position in the active site provided by the telomerase reverse transcriptase (TERT). This step might require the formation of guanine-rich secondary structures in the nascent product. Results from numerous studies begin to delineate TERT sub-domains that orchestrate these events and support the model of cooperative action between distinct active sites within telomerase multimers. Natural telomere substrates are protein-DNA complexes that show an asymmetry between the two ends of a chromosome, possibly reflecting their differential mode of replication.