The tie remains firmly in the balance following a goalless draw between the sides in Turkey last week.
Shakhtar welcome Fenerbahce to Ukraine on Wednesday having earned what could be a precious 0-0 draw in Turkey.
Following an even 90 minutes at the Sukru Saracoglu Stadium in Istanbul, Mircea Lucescu's side will have been pleased to return home with a clean sheet and everything to play for.
However, the second leg will not be held at their traditional home at the Donbass Arena due to safety concerns. The game will instead be played at the Arena Lviv.
"We should play for a win and focus on our opponents," attacking midfielder Taison has said in the build-up to the game. "We are producing good results in Ukraine and want to be positive in the UEFA Champions League, too. We are ready for different scenarios, but we still want to score in 90 minutes."
Shakhtar have already started their Ukrainian Premier League campaign, with three wins from three matches putting them at the top of the table early on.
Their most recent outing in the league came on Saturday when they recorded a comfortable 2-0 triumph over Hoverla. Alex Teixeira was on target for the hosts to make it five goals already this season for the Brazilian.
Recent form: D
Recent form (all competitions): WWWWDW
With their domestic season yet to start, Fenerbahce have been in solid form so far this summer.
Vitor Pereira's side beat Voluntari and Marseille in friendlies last month, while their goalless draw with Shakhtar added to their encouraging unbeaten run.
Despite winning five pieces of silverware in the last five seasons, the Turkish outfit have struggled when it comes to European competition.
They enjoyed a run to the semi-finals of the Europa League in 2013, but the last time that they reached the Champions League group stage was back in 2009.
Fenerbahce may well feel like they did themselves no favours by drawing at home to Shakhtar in the first leg. True, they have it all to do in Lviv, though they will also be well aware that everything is still up for grabs.
Recent form: D
Recent form (all competitions): LDWWWD
Shakhtar have been told by UEFA that midfielder Fred will be eligible to play despite the Brazilian failing a doping test at the Copa America.
Fenerbahce lodged a complaint with the governing body after Fred featured in the first leg, but UEFA has cleared Shakhtar of any wrongdoing.
Meanwhile, summer signing Robin van Persie is expected to start for the visitors following his move from Manchester United. Both teams have no fresh injury concerns heading into the game.
Shakhtar Donetsk possible starting lineup:
Pyatov; Srna, Ordets, Rakitskiy, Shevchuk; Marlos, Fred, Stepanenko, Taison; Alex Teixeira, Gladkiy
Fenerbahce possible starting lineup:
Demirel; Kaldirim, Bruno Alves, Kjaer, Erkin; Nani, Topal, Souza, Diego; Van Persie, Sow
Head To Head
This will be just the second time that the teams have faced off following their draw in Turkey one week ago.
We say: Shakhtar Donetsk 2-1 Fenerbahce
Despite playing the match away from their own stadium, 'home advantage' for Shakhtar could play a huge role in determining who goes through. Both teams have plenty of talent to call upon, but the fact that the hosts have already started their league campaign could also be a big factor in the tie. While it could be a close second leg, Shakhtar should be considered favourites to progress.