Luis Fernando Tena's side have made a dream start to the campaign, winning five of six and scoring 13 goals to be three points clear.
They host 12th-placed Puebla on Saturday and will fancy their chances of at least maintaining their buffer at the top.
Marco Fabian and Mauro Formica have been the key to Cruz Azul's goal-scoring ways, netting three times each.
They crushed Atlante 4-1 last time out and should be too good for a Puebla side who have won just once in the league this season.
Toluca are unlikely to give up any ground as they travel to lowly Veracruz, also on Saturday.
With four goals, Pablo Velazquez has been a shining light for Toluca, who should ensure the league's second bottom side continue to struggle.
America will be looking to bounce back from their loss to Pachuca when they travel to Morelia on Friday.
After scoring just seven times in six league games, America need to start finding the net more or risk slipping down the table.
Apertura champions Leon have made a poor start to the Clausura campaign and visit Monterrey on Saturday.
Carlos Pena may be in decent form up front, but Leon are winless in four outings to be 14th on the table.
Elsewhere, Pumas UNAM will be aiming for their fourth straight league win when they host Atlas, while Atlante visit Pachuca.
Queretaro and Guadalajara do battle on Sunday, Tijuana visit mid-table Santos Laguna and Chiapas need to find some consistency when they host Tigres UANL.
