Argentina's clash with Colombia in Buenos Aires catches the eye, as the leaders take on the third-placed team in the nine-strong pool, with the prospect of Lionel Messi engaging in a shoot-out with Radamel Falcao.
There is some doubt over Messi's involvement, as Barcelona's world player of the year has been troubled by a hamstring injury, and Argentina boss Alejandro Sabella has vowed to take no risks over the 25-year-old's fitness.
Argentina hold a four-point cushion over second-placed Ecuador, who are in turn one point clear of Colombia, but Sabella's men have played one more game than both their nearest rivals.
Ecuador are pushing hard for a place in what would be just their third World Cup, and they face a trip to Peru for a clash at the Monumental Stadium in Lima.
Peru are stragglers in seventh place on 11 points at present, but have time to improve.
The leading four teams after 16 rounds of games go through to the finals, the first South America will have staged since Argentina put on the 1978 tournament, with the fifth-placed side entering a play-off against a team from Asian qualifying.
Ecuador boss Reinaldo Rueda will hope his side can make it through without needing a play-off, and they are set to be at full strength.
Midfielder Pedro Quinonez said: "We know Peru are tough opponents. If we do not take the necessary precautions, they will surprise us. We are focused on not making silly mistakes."
Peru head coach Eduardo Markarian considers the match a "life or death" tussle - and then Colombia await his team next Tuesday.
"It is clear that we face two of the hardest teams, that are among the best 10 in the world. It will be hard, but not impossible and we do not lose our faith," said Markarian.
Ecuador, Colombia and Peru have each played 10 rounds of games, with the other sides having 11 matches behind them.
Paraguay are at the foot of the table but still clinging to hope of making it to Brazil.
Manager Gerardo Pelusso believes they must take advantage of being at home against fourth-placed Chile, saying: "We have five games ahead, four of them as hosts. That shows that we can make it, our chances exist and we will fight for them. The squad is united and I hope that the fans support us."
Chile coach Jorge Sampaoli said: "It will be a high-tension game. We have to be ready to face a clash with excessive intensity. Paraguay have their last chance and they have players who can cause damage. Today, we are 50% per cent in the World Cup and we have to look for the other 50 per cent playing our best football."
Venezuela stand fifth, alongside Chile on 15 points, and their clash with eighth-placed Bolivia in La Paz has been given added spice.
It came in the form of an outburst from former Bolivia player Marco Antonio Etcheverry, who assists boss Xavier Azkargorta.
Etcheverry said: "The Venezuelans are good at producing soap operas and beauty queens. I have to congratulate them for that, but not for playing football. They will leave our venue on their knees."
Responding to the mud-slinging, Venezuela boss Cesar Farias said: "We are sorry about the Bolivian coaching team's derogatory expressions. We respect the past, but we work ahead to the present and future."
Bolivian FA president Carlos Chavez added: "We respect Venezuela, but we can beat them. Bolivia have been to a World Cup, been runner-up in the Copa America and taken part in the Confederations Cup and they haven't."