Most of the Cretaceous and Cenozoic deep-water oil and gas fields are distributed in Sao Paulo High, and others in depressions in the slope, Santos Basin. The development of regional Lower Cretaceous evaporite seal ensures the entrapment of hydrocarbon in the sub-salt sequence. Based on studies on the structural framework of the basin and the features of source rocks, reservoirs and hydrocarbon distribution, the Santos Basin is divided into two petroleum systems, the Lower Cretaceous one and the Upper Cretaceous one. The Lower Cretaceous petroleum system can be further divided into the post-salt and pre-salt plays. Subsequently the extent of petroleum systems is delimited. It is suggested that the pre-salt lacustrine carbonate rock in Lower Cretaceous Guaratiba Group on the Sao Paulo High is of the greatest exploration potential. The turbidite of Turonian Ilhabela Member and the turbidite within Cenozoic Marambaia Formation in the northern and central parts of the basin rank the second, and the marine carbonate rock of Lower Cretaceous Guaruja Formation in the southwestern part of the basin is also a certain exploration potential.