The pair, along with Maryland former governor Martin O'Malley, take the stage in Charleston, South Carolina with the temperature rising in the primary battle.
All three are aware that their performance -- the final Democratic debate before the Iowa caucuses on February 1 -- could have a crucial impact on who wins the state.
Establishment Democrats are wary of a repeat of 2008, when Clinton led all rivals into the Iowa home stretch, only to lose the state to little-known senator Barack Obama, who pulled the rug out from under his rival and eventually won the nomination and the White House.
Clinton is the presumptive favorite again. But last year's scandal about her use of a private email account and private server while secretary of state has lingered, and her favorability ratings are lower than those of Sanders.
O'Malley, despite stage time with the other candidates, has made no substantial headway in polls and is seen by many as an also-ran.
While leading nationally, Clinton suddenly finds herself under threat of losing the first two state contests, in February 1 in Iowa, where the pair are neck and neck in the polls, and February 9 in New Hampshire, where Sanders has a significant lead.
All too aware of the Sanders surge, Clinton sharpened her offensive against him this past week, highlighting their policy differences with the self-declared democratic socialist on guns, health care and taxes.