In recent years, the flexible piezoresistive pressure sensor has attracted widespread attention due to the trend of improved wearable electronics applied to the field of electronic skin, disease diagnosis, motion detection and health monitoring. Here in this paper, the latest progress of the exploitation of flexible piezoresistive pressure sensors is reviewed in terms of sensing mechanism, selection of sensing materials, structural design and their advanced application. Firstly, the sensing mechanism of piezoresistive pressure sensors is generally introduced from the band structure of semiconductor materials, seepage theory and tunneling effect of conductive polymer composites and changes in interface contact resistance. Based on these sensing mechanisms, various flexible piezoresistive pressure sensors with high sensitivity, broad sensing range and fast response time have been developed. The selection of composition materials and microstructural design in flexible piezoresistive pressure sensor to implement the optimization of sensing performance are emphatically presented in this review. The composition materials including organic polymer material and inorganic nanomaterial based on two-dimensional (2D) materials such as graphene and MXene are intensively exhibited. In addition to the above characteristics, these kinds of pressure sensors exhibit high mechanical reversibility and low detection limit, which is essential for detecting the minor motions like respiratory rate and pulse. Moreover, the well-designed structures applied to the composition analysis are also overviewed, such as the sea urchin-like structure, spongy porous structure and regular structure. Various designed structures provide further properties like stability for the flexible pressure sensor. However, comparing with traditional pressure sensor, the mass production and application of flexible pressure sensor are confronting several barriers, like the high cost of raw materials and relatively complex manufacturing processes. How to achieve the low cost and low energy consumption simultaneously on the basis of excellent performance is still a challenge to expanding the applications of flexible pressure sensor. Novel sensing mechanism, functional materials and synthetic integration are expected to be developed in the future. And also, the potential application of flexible pressure sensor will be further expanded after endowing it with more functions.