The authors studied the spatial distribution of built-up area for 5 major cities in the Pearl River Delta Region in recent 40 years, based on multi-source and long-series satellite images and GIS technique, and the 5 major cities are: Guangzhou, Shenzhen, Zhuhai, Hong Kong and Macao. Spatial-temporal dynamic characteristics and driving factors for the built-up sprawl are analyzed. The speed of built-up sprawl for the 5 major cities overall is relatively faster in the 8th “5 Year Plan” period (1991–1995) and the 10th “5 Year Plan” period (2001–2005). The spatial pattern of Guangzhou and Shenzhen’s built-up characterizes with axial and zonal group, while for Zhuhai, Hong Kong, Macao are abundant of islands, the built-up is sprawled by leaps and forms multi urban centers. Urban expansion in the Pearl River Delta Region has the largest influence on farmland, followed by the forestland, and again the construction land for rural residential or industrial use. Because of reclamation projection, the sea area supplies more land resource for built-up expansion in Hong Kong and Macao. Terrain conditions, transportation development, policy making, population and economic growth are important driving factors for urban expansion in the Pearl River Delta Region. The sequence of built-up area’s expansion ratio is coincidence with the population increase rate and GDP increase rate for the 5 major cities, of which the values of Shenzhen are the largest of all, and then followed by values of Zhuhai, Guangzhou, Macao, and Hong Kong in sequence.