Great progress has been made in the generation of ultrashort laser pulses in the mid-infrared (MIR) band of femtosecond laser by intra-pulse difference frequency technology, and it has been widely used in physics, chemistry, biomedicine, and other scientific areas. Firstly, the development and research background of MIR laser are introduced. Then the basic principle of intra-pulse difference frequency generation (DFG) of femtosecond laser is introduced. The progress on MIR pulse generation by intra-pulse DFG with different driving sources, such as Ti:sapphire laser, femtosecond laser at 1 μm waveband, femtosecond laser at 2 μm waveband, and fiber laser, is reviewed and compared. Finally, the future developments of the MIR femtosecond laser generated by intra-pulse DFG are prospected.