Schalke have endured a dire start to their league campaign and are bottom of the table on goal difference, having lost both of their opening two fixtures, and will not be looking forward to their trip to Leipzig.
Leipzig have finished second or third in three of their last four Bundesliga seasons - finishing sixth the other year - and once again look like one of the best teams in the division.
They boasted the second-best defence in the league last term and scored an impressive 81 goals in 34 games, but were held back by failing to convert draws into wins.
Leipzig only lost four league games last season - the same number as eventual champions Bayern Munich - but their 12 draws was the joint-highest tally in the Bundesliga.
They were held again in their last outing by Bayer Leverkusen, and exciting young manager Julian Nagelsmann knows his side must be more ruthless and turn one point into three more consistently if they are to truly challenge for the league title.
Schalke have much bigger problems, however. They last won a Bundesliga game in January and are on an 18-game winless run in the competition.
Head coach David Wagner was relieved of his duties after their last match - a 3-1 home defeat against a Werder Bremen side that barely avoided relegation last season and were missing Milot Rashica - and have appointed former Augsburg manager Manuel Baum to replace him.
Baum's first game of an unenviable job is a difficult test, and the new boss may look to simply limit the damage and avoid a repeat of the 8-0 hammering by Bayern Munich that Schalke suffered on opening day.
The club's subsequent league outing against newly-promoted Union Berlin at home may prove a more realistic target to end their winless streak.
RB Leipzig Bundesliga form: WD
RB Leipzig form (all competitions): WWD
Schalke 04 Bundesliga form: LL
Leipzig boss Nagelsmann has a fairly lengthy list of absentees ahead of the visit of Schalke, including a number of key players.
Fabrice Hartmann is also out with an ACL injury and will not be back this calendar year.
New Schalke manager Baum is missing just three players ahead of the trip to Leipzig.
RB Leipzig possible starting lineup:
Gulasci; Mukiele, Upamecano, Klostermann; Haidara, Adams, Kampl, Tasende; Olmo, Forsberg; Sorloth
Schalke 04 possible starting lineup:
Fahrmann; Rudy, Sane, Stambouli, Oczipka; Mascarell, Bentaleb; Boujellab, Uth, Raman; Paciencia
We say: RB Leipzig 2-0 Schalke 04
Leipzig should win this comfortably, but may be denied a big scoreline by the absence of their regular striker and the fact that new Schalke boss Baum may instruct his side to sit deep and play for a point.