Complex pressure system existing in stratum will bring serious challenge to well drilling engineering. There are different stratums with high collapse pressure, high pore pressure, pressure depletion and low leakage pressure in Weizhou 12-1 Oilfield. The main difficulties existing in well drilling are collapse of shale with bedding and cracks in upper formation of the Weizhou 2^nd section and coexistence of abnormal high pressure and low pressure formations in the Weizhou 4^th section and well drilling liquid loss is easy to occur in abnormal low pressure formation. Results obtained from rock mechanics analysis show that collapse of the Weizhou 2^nd shale is mainly controlled by weak bedding planes and wellbore is more stable in the case of drilling with smaller inclination angle. Both of collapse pressure and leakage pressure will decrease along with pore pressure drop in the Weizhou 4^th reservoir. Based on the above analysis, safe density window with drilling depth is established and safe drilling design principles are put forward. In well track design, low deviation angle shall be chosen in shale of the Weizhou 2^nd section. In the Weizhou 4^th reservoir, the high pressure differential shielding drilling fluid system and as far as possible low fluid density shall be selected to reduce the risk of wellbore instability.