Holder Warrington will begin its defence of the Challenge Cup against Championship club Featherstone Rovers.
The Wolves, who beat Huddersfield at Wembley last August, will have home advantage in the fourth round on the weekend of April 16-18.
The outstanding tie of the last 32 pits Super League champion Leeds against Super League rival Hull at the KC Stadium in a repeat of the 2005 final which was won by the Black and Whites.
"It's a tough draw," said Leeds coach Brian McClennan. "We'll have to perform very well to beat Hull on their ground."
The Hull-Leeds tie, which is a repeat of the 1910 final which was won by Leeds, is one of four all-Super League clashes.
Last year's runner-up Huddersfield is at home to Hull KR while Wakefield visit Harlequins and Catalans Dragons host Salford.
Wigan meet Sheffield Eagles in a repeat of the famous 1998 Wembley final while St Helens, which won the trophy four times in a row up to 2008, is at home to Championship club Toulouse, one of four French clubs in the last 32.
"It's fair to say it's a favourable draw," said Saints full-back Paul Wellens.
Leigh must travel to Limoux while Widnes will be at home to Lezignan providing they overcome amateurs Wigan St Judes in a delayed third-round tie on Tuesday night.
Siddal, the only amateur club definitely in the fourth round, has landed a home tie against Batley.
McClennan, whose side lost 22-18 to St Helens in round four last season, hopes his side does not come unstuck at the KC Stadium this time around.
"It's part of the drama of the Challenge Cup that there are some tight encounters and exciting draws, he said.
"We'll take it one game at a time and that's all you can do. It's one hell of a challenge, going to Hull and playing them at their ground.
"We won't be looking any further than the first minute of that game and making sure we're in there competing and putting in a good performance and if we don't we'll be out."
Wolves coach Tony Smith, who took less than six months to end Warrington's 25-year wait for a major trophy when it beat Huddersfield 25-16 at Wembley, said: "That's a tough draw, tougher than most people would think.
"They are one of the favourites from the division below so it will be a tough fixture for us."
Smith admitted last year's triumph should provide the necessary motivation for it to make a similar push in this season's competition.
He added: "The will to go back and do it again is great from all of us. For the fans, players and coaches, that would be fantastic.
"It's a new year and you have to start all over again. Just by having the experience doesn't necessarily mean you are going to go back there again.
"It gives you a taste of what it's like and Wembley is certainly a special place. We'll be fighting to go back again."