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If you're looking for hints and tips on who to pick, we'll be running a regular blog every Friday at Football.co.uk - and the fun starts right here.
Remember there are three transfer windows during the season and you can shuffle your substitutes on a weekly basis to make sure you don't waste injured picks - and make the most of form players.
Here are our suggestions for week one.
Edwin van der Sar (5.34) looks a great pick out of the blocks. Manchester United conceded the least goals in the Premier League last season and the Dutch stopper is an extremely consistent performer. With visitors Newcastle fresh from life in the Championship, it should be a comfortable start to the new season at Old Trafford.
Petr Cech (6.29) is also a good bet for a clean sheet as Chelsea entertain West Brom.
Tim Howard (7.56) is expensive, and might be best avoided if you consider he conceded twice in Everton's 3-2 win at Blackburn last season.
Thomas Vermaelen (5.20) of Arsenal offered up seven Premier League goals last season and should prove a popular pick. As visitors to Anfield on Sunday, the Gunners will fancy themselves for a clean sheet with Fernando Torres still out.
How about Ryan Shawcross (3.86) to partner him. The Stoke defender impressed last season and will see his side travel to Wolves on Saturday - who scored just 32 times in 38 games last season.
Wilson Palacios (4.49) could be a decent option. Tottenham face Man City, having won both league games against City last season without conceding a goal.
Scott Parker (4.52) of West Ham had a great season last year, and with Aston Villa reeling after Martin O'Neill's exit he could play a key role in an away day win for the Hammers.
It's hard to look beyond Didier Drogba (6.84) and Nicolas Anelka (7.01), who will fancy themselves to get in the goals for champions Chelsea against West Brom at Stamford Bridge.
Bobby Zamora (5.22) is also worth a look, as Fulham take on Bolton. The striker should be full of confidence after playing for England in midweek.