It's back to the road, for the fifth time in the first seven weeks of the season. The Bills are at work this week trying to bounce back from last week's discouraging loss in Houston.
Here are the top storylines as the Bills get set to take on the Indianapolis Colts:
1. NEW MAN UNDER CENTER
Derek Anderson becomes the third man to start at quarterback for the Bills in the first seven games this season, named to the position Wednesday morning.
The 35-year old veteran was just signed to the roster 8 days ago, signed as a seasoned mentor for rookie Josh Allen. But with Allen's elbow injury and the inconsistent play of QB Nathan Peterman, the Bills turn now to Anderson.
He's started 47-games in his 14-year NFL career, the last one two years ago. While with Carolina in 2016, in week 13 against Seattle, Anderson started and played one play when Cam Newton was benched for violating the Panthers dress code.
Bills Offensive Coordinator Brian Daboll says Anderson has been cramming this week, getting up to speed on the Bills playbook.
"He's picking it up," Daboll says. "To come off the street and come in, he's upstairs right now, he's upstairs all the time. I don't think you can put the whole thing on him. He's played a long time, so concepts are concepts. It's understanding the language. He's grinding it out."
2. CAN THE DEFENSE KEEP IT UP?
It has been an amazing turnaround in the first half of the season for the Bills defense. After giving up 78 points in the first two weeks of the season, the Bills have shut the door. Opponents have averaged 15-points per game against the Bills since week three and the Bills have split the last four games.
The Buffalo defense is now ranked 3rd overall in the NFL and is in the top ten in rushing yards allowed, passing yards allowed, and sacks.
Veteran DT Kyle Williams says the Bills made it a focus to start games faster on defense and it's paying off.
"I think we've started games better than we had," Williams said this week in an appearance on One Bills Live. "And it's a product of things not snow-balling, like the Baltimore game."
"Collectively, we've played better as a team. And we cleaned up some of our errors on defense. We have some young players, some guys that haven't played before in the NFL. They're only going to get better the more they play."
3. COLTS HAVE LUCK ON THEIR SIDE
He's back. After missing all the 2017 season following shoulder surgery, Indy QB Andrew Luck is back and healthy as ever. He's completed 65-percent of his passes for 16 touchdowns and eight interceptions so far.
And the Colts have put him to work. Luck has 288 pass attempts in six games, on pace to finish the year with 768 attempts. That would be a new NFL record for pass attempts in a season.
The same for completions. He's got 186 of them, on pace for 496 completions, which would break Drew Brees' record set two years ago.
But Indy hasn't translated Luck's arm into success. Their passing attack is 10th in the NFL this year in terms of yards produced. And last Sunday's Colts loss to the Jets marked the first four game losing streak of Andrew Luck's seven-year tenure.
4. LUCK'S GOT REICH ON HIS SIDE
Former Bills QB Frank Reich has a Super Bowl ring on his finger, and a solid resume as he works through his first year as Colts Head Coach. His team has just one win in their first six games, but Reich is as steady as ever.
Reich, who interviewed for head coaching vacancies in Buffalo in recent years, finally got his chance last March, when the Colts first candidate, Josh McDaniels, pulled out after accepting the post.
Reich is an all-time hero in Buffalo, mostly for engineering the NFL's greatest comeback 25-years ago, when the Bills beat the Oilers in a Wild Card playoff game. But his 10-years playing in Buffalo, and his continuing presence in the area have produced thousands of fans and admirers in Western New York. Reich comes back to Buffalo every spring to host the "Call to Courage" Awards Breakfast to benefit Athletes in Action.
5. REICH'S NOT THE ONLY WNY CONNECTION
The Colts have several Western New York connections, including Offensive Coordinator Nick Sirianni, a native of Jamestown. He's spent the last ten years coaching in the NFL with the Chiefs, the Chargers and now the Colts.
Longtime Bills Strength and Conditioning Coordinator Rusty Jones is back in the NFL, now the Colts Director of Sports Performance. And former Sabres Strength and Conditioning Coach Doug McKenney is now Assistant Strength and Conditioning Coach for Indy.
6. OPPORTUNITY FOR THE BUFFALO OFFENSE?
The first third of the season has been a struggle for the Bills offense. They average 13 points scored per game. Buffalo ranks last, or second to last, in most major offensive benchmarks.
But the Indianapolis Colts may be just what the Bills need. Indy gives up 30-points per game. They struggle defending the pass. It could be a chance for the Buffalo offense to show some signs of life this week.
The Colts have been opportunistic. They've got 17 sacks on defense and six interceptions, putting them in the top 10 in the league in both categories.
7. END OF THE LONG ROAD HAUL
It's the second straight road game for the Bills, another one against an AFC South opponent. And it's the end of Buffalo's brutal seven game stretch on the road.
The Bills played five of their first seven games away from home this year. They're home next Monday against the Patriots. Six of the Bills final nine games will be at home.