First team captain Allister Hogg switches across the back row to openside to fill the gap left by Rennie's absence with Cross getting the nod to start at blindside.
The centre pairing of Ben Cairns and Nick De Luca remains intact for the visit of the Welsh club after both players passed fitness tests today.
In the second row, Matt Mustchin, who scored a try during last week's bonus point victory over Connacht, has been selected in the starting line-up with Ben Gissing and Fergus Pringle named amongst the replacements.
Meanwhile, No8 David Callam admits fourth-placed Edinburgh are determined to finish the season with a flourish after suffering late slumps during previous campaigns.
Callam said: "We have been in this position a couple of times before, but for some reason we have always fallen away poorly after the 6 Nations.
"That is something that we're working hard on addressing this year. Guys are fed up of the fact that we work hard to get ourselves into these positions and never take advantage of it.
"Beating Connacht was the start, but we need to push on and win our home games if we want to finish as high up the league as we can.
"Cardiff have named a very strong side and we know it will be a tough match.
"But we are planning to play the same type of high-tempo rugby that brought us the bonus point win against Connacht."
Apart from the loss of Rennie, Edinburgh are also without hooker Ross Ford (ankle), prop Allan Jacobsen (groin), winger Roland Reid (hamstring) and Alan MacDonald (fractured cheekbone) while Greig Laidlaw, Alistair Warnock and Scott Newlands are away on international duty with Scotland 7's in Hong Kong.
Edinburgh Rugby Club squad to play Cardiff at Murrayfield (Friday 28 March, kick-off 7.30pm):
15 Hugo Southwell
14 Simon Webster
13 Ben Cairns
12 Nick De Luca
11 John Houston
10 Phil Godman
9 Mike Blair
1 Gavin Kerr
2 Andrew Kelly
3 Craig Smith
4 Matt Mustchin
5 Craig Hamilton
6 Simon Cross
7 Allister Hogg (captain)
8 David Callam
Substitutes: Steve Lawrie, Augusto Allori, Fergus Pringle, Ben Gissing, Ben Meyer, Calum MacRae, Andrew Turnbull.
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