Maybe this year luck is on the 49ers' side but they'll have to get past their old rivals a possible three times yet again just to reach the Super Bowl. Either way, one of these sides should be there but don't count out the New Orleans Saints or the Green Bay Packers.
Brady, Manning on last legs
The clock is ticking on Peyton Manning and Tom Brady. The two quarterback greats are well into their late 30s, which signals the end is nigh for two very impressive careers - only one quarterback (John Elway) has won a Super Bowl after turning 38.
The scoreboard has Brady (37) - won three Super Bowls and lost two - still ahead of Manning (38) - won one and lost two. If either man is going to claim another ring, this year may well be their final chance.
Following last season's embarrassing 43-8 defeat to the Seahawks in Super Bowl XLVIII, Manning will be even more determined to add to his legacy by getting to the sport's showpiece game for a fourth time - and winning it again. Brady's last appearance in the Super Bowl wasn't as poor as Manning's but the Patriots' 21-17 loss to the Giants in XLVI wasn't exactly a typical Brady performance either as he was simply outplayed.
A second straight meeting between the two veterans in the AFC championship game isn't too far-fetched, with neither side taking a seemingly backward step in the off-season. Both the Broncos are Patriots are in weak divisions are if they do somehow give up the division title, should still grab a wildcard spot. But whether Brady can break a 10-year title drought, or whether Manning will win his second title since 2007, is another question. Time is ticking.
Johnny Football
The next RG3 or the next Tebow? Either way, the mercurial Johnny Manziel is set to steal a disproportionate number of headlines when he gets on the field with the Cleveland Browns.
Manziel, a gifted runner with a questionable arm, was taken by Cleveland with the 22nd pick in the NFL draft, the second quarterback to be selected. It was the type of pick that suggested not even the experts knew whether Manziel would emulate Robert Griffin III's outstanding rookie campaign, or whether he would flame out of the league like now-ESPN analyst Tim Tebow.
In addition to uncertain professional prospects, Manziel will bring to the NFL his fair share of baggage. The 21-year-old's college career with Texas A&M saw him break numerous records and become the first freshman to win the Heisman Trophy, awarded to the nation's top player, but it also saw him earn unwanted attention outside the lines.
A late-night fight leading to an arrest, regular appearances at frat parties and a close relationship with rapper Drake led many to wonder if Johnny Football was letting his new-found fame go to his head.
Whether that behaviour will be tolerated in the NFL will depend largely on his performances. First, though, Manziel must usurp Browns starting quarterback Brian Hoyer. Until then, he will merely be the most talked about back-up in the league.
Suspensions
Ray Rice (Ravens), Aldon Smith (49ers), Josh Gordon (Browns) and Robert Mathis (Colts) are among 31 players who start the season under suspension for a variety of reasons, from substance abuse to 'conduct detrimental to the league'. Denver Broncos wide receiver Wes Welker was the latest, hit with a four-game suspension on Tuesday for breaking the league's policy on performance-enhancing drugs. And it hasn't just been the players - Colts owner Jim Irsay was handed a six-game suspension and a US$500,000 fine after a drink driving charge.
The fines total more than $8m so, despite the bad press, it's at least been a windfall for the NFL. Here's a full list of suspensions and fines. But which player is a bigger loss?
Gordon, sidelined for a year, will be a huge blow for the Browns. He led the league in receiving yards last season, scoring 15 touchdowns in the process. He was expected to be a big target for Manziel who is now stuck with a past-his-prime Miles Austin, formerly of the Cowboys, and a quartet of untested receivers - one of whom, Marlon Moore, is suspended for the first game.
The absence of Rice and Smith will have bigger impacts for the two teams who squared off in the Super Bowl two seasons ago. Smith is a large part of a 49ers defence that came within a game of making a second straight Super Bowl. It will be hard to stay with division rivals Seattle with the linebacker sitting out the first nine weeks.
Michael Sam
Practice squad players don't typically hold press conferences upon signing with a new team. But Michael Sam, now with the Dallas Cowboys, is no typical practice squad player.
Sam is attempting to become the first openly gay athlete to play in the NFL and, after being released by the St Louis Rams, it looks like he may get a chance to make history in his native Texas.
The 24-year-old did just that when he was selected by St Louis in the seventh round of this year's NFL draft, but he was unable to survive the cuts when the roster was trimmed to 53 players. The Rams were too deep at defensive end and Dallas, where Sam signed a few days later, appears far weaker in the pass-rushing positions.
The University of Missouri stand-out still has to make it from the Cowboys' 10-man practice squad onto the gameday roster - and then the real intrigue starts. Misguided questions of Sam being a distraction in the locker room have already been raised, and while Cowboys quizzed on the topic have so far been making the right noises, the team will hopefully have a chance to walk the talk sooner rather than later.
Super Bowl prediction
Cameron McMillan: 49ers v Chargers
Kris Shannon: Seahawks v Patriots
