What an odd question. I scrolled through and saw some have already answered my first thoughts: Harry/Hermione in Harry Potter, Clarice Starling/Dr Lecter in Silence of the Lambs, Leslie/Ron in Parks and Rec... Also, almost all of the CSIs had a hetero male lead/hetero female lead character setup, and barring Grissom/Sidle in the early years of original CSI (although one could argue if Marg Helgenberger was the female 'lead' here), the rest of the combos - the Laurence Fishburne seasons, the Ted Danson/Elizabeth Shue in CSI's later years; Caruso/Procter in CSI: Miami (I don't think happened, I haven't watched all of Miami); Sinise and either Melina Kanakaredes or Sela Ward in CSI: NY; Arquette in CSI: Cyber... Also, pretty famously, with fans and/or the press asking again, now that Meloni has got his own show, Law & Order: SVU never went there with Hargitay/Meloni when both were on SVU for its first (12?) seasons. Likewise D'Onofrio and Erbe on L&O: Criminal Intent never happened.
Your friends can seriously not name ONE piece of entertainment where the leads do not get together?