The tournament kicks-off tonight with two classic Welsh derbies - Aberavon go to Parc y Scarlets to face Llanelli while Pontypridd travel down the A48 to face Cardiff at the Arms Park.
Neath, meanwhile, host former Guinness Premiership outfit Bristol at The Gnoll and Newport entertain the current leaders of the English Championship, Exeter Chiefs, at Rodney Parade.
"Exeter will be coming on the back of a run of 11 successive wins in the English Championship. We know it is going to be tough for us to play against full-time professionals, but the players can't wait to get stuck into them," said Newport coach Sven Cronk.
"We will definitely be going after them in the game and we want to see just where we stand against the top teams at our level in England."
That is a familiar goal for all the Welsh sides, who have been locked in local battles since the professional game went Regional some six years ago. The introduction of cross-border competition - Munster, Leinster and Ulster are putting in their A teams and there are two Scottish club sides and their National Academy taking part - will finally give the top six Principality Premiership teams contact with their counterparts across the Severn bridge and over the Irish Sea.
"We have a very tough challenge ahead of us in Bristol, but it is a challenge we relish," admitted Neath coach Pat Horgan
"The opportunity to take on a fully-professional, all-star English club at The Gnoll is not to be missed and I hope that our supporters are up for the challenge too. There can be no under-estimating just how big an opportunity this competition will be for Neath and all the other Welsh clubs. But it is a tournament that we have lobbied hard for as it will test our players in a new environment against different players and different styles of play."
Pontypridd's home fixture with arch-rivals Cardiff has been switched to the Arms Park because of the waterlogged pitch at Sardis Road, but there are likely to be plenty of Ponty voices singing on their heroes.
"This is a great opportunity for our players to get out of the comfort zone that has grown around the Principality Premiership. We all know each other so well in the tournament, but now we will be stepping into the unknown," said Ponty coach Paul John.
"I know we are starting with familiar foes in Cardiff but, in many ways, it couldn't be better because it is such a big game for both clubs.
Exeter Chiefs (v Newport): S Marsden; N Sestaret, B Rennie, T Bedford, P McKenzie; D Gray, C Stuart-Smith; B Moon, S Nelson, R Murphy, S Tomes, J Hanks, A Miller (captain), A Miller, M Stupple. Replacements: J Andrew, S Blythe, T Freeman, L Calder, D Ewers, R Bolt, M Cornwell
Neath (v Bristol) G.King; K.James, S.Thomas, W.Mitchell, K.Morgan; A.Thomas (captain), K.Farrell; N.Downs, G.Price, M.Jones, P.Sidoli, N.Edwards, E.Evans, L.Evans, G.Gravell. Replacements: A.Jenkins, G.McCarthy, T.James, A.Littlehales, J.Reeves, H.Pugh, C.Price