Spain and Portugal both face marathon trips with the world and European champions travelling to Panama and their Iberian neighbours lured to oil-rich Gabon where Cristiano Ronaldo's presence is awaited with feverish excitement.
There are high-profile games between familiar European rivals, such as Netherlands-Germany, Italy-France and Sweden-England, and more exotic encounters such as the clash between Albania and Cameroon in Geneva.
Steven Gerrard is in line to make his 100th appearance for England while Rene Adler, set to be Germany first-choice goalkeeper at the last World Cup until he was injured shortly before, is back in squad, two years after his last appearance.
Only a few years ago, Cameroon would have been favoured opponents for many of the world's top sides.
But, beset by internal bickering, their fortunes have taken a dramatic turn for the worse which culminated with elimination from the African Nations Cup at the hands of tiny Cape Verde, who themselves face Ghana in Lisbon on Wednesday.
In other games, Franco Di Santo could make his international debut as Argentina, including Lionel Messi and Sergio Aguero but missing out-of-favour Carlos Tevez, visit Saudi Arabia while Russia meet the United States for the first time in 12 years.
Brazil's meeting with Colombia at the Metlife stadium in New Jersey brings two together two sides who have reaping the rewards of a more positive, attacking approach in the last few months.
Brazil's search for their ideal team and a playing style which better suits their tradition appears to be bearing fruit for coach Mano Menezes, who has been greatly helped by the return of Kaka following a two-year absence from international football.
They scored 10 goals in two games against Iraq and Japan last month as the Oscar-Kaka combination in midfield and the exuberant skills of Neymar in attack proved irresistible for their opponents.
The 2014 World Cup hosts and five-times winners have won their last six games and face by far their sternest test since they lost 4-3 to Argentina in June, their last defeat.
Colombia, a team struggling to find their footballing identity ever since their 1994 World Cup fiasco, have come back to life under the leadership of Argentina's 2006 World Cup coach Jose Pekerman.
They have won six out of seven matches under the former taxi driver including a 4-0 win at home to Uruguay and 3-1 win in Chile, putting them firmly on course for their first World Cup appearance in 1998.
The meeting of Santos forward Neymar, who has scored 16 goals in 25 internationals, and Atletico Madrid's Falcao, both on the radars of Europe's top sides, has added extra spice to the encounter.
"Colombia have had a great qualifying campaign and will be a good test for us to know where we are now," said Menezes. "They have a touch of Argentina about them. They had a lot of quality before but they now they are showing far greater tactical development."
Spain, who have made a habit of visiting far-flung ex-colonies recently, follow up trips to Venezuela, Puerto Rico and Costa Rica with their game in Panama on Wednesday.
It will not be a walkover for Spain against opponents who have reached the final stage of the CONCACAF World Cup qualifying competition and whose coach Julio Cesar Dely Valdes spent part of his playing career at Real Oviedo and Malaga.
"The trip to Panama is part of a commitment by our country with other Spanish-speaking nations and, in sporting terms, allows us to prepare for upcoming matches," said coach Vicente del Bosque.
Portugal can expect a festive reception in Gabon where President Ali Bongo, a fervent football fan, is almost certain to be among the crowd.
His government has spent lavishly on football projects, allowing the country co-hosted this year's African Nations Cup and played at home to Brazil one year ago.
Gabon's Portuguese coach Paulo Duarte, known as the African Mourinho, became famous for his post-match rants during a previous spell with Burkina Faso, usually aimed at his own directors.
The match has created logistical problems for Portugal coach Paulo Bento, who will have only one training session with his players on Tuesday and was unable to select anyone from Benfica who are playing the following Friday.