S21 is similar to a voltage gain. Technically, it is the ratio of transmitted/incident "wave amplitudes".
Since on a transmission line, you can have forward and reverse travelling "wave amplitudes", you can not simply call them "voltages" since you can not measure them at a point with something like a pyhsical voltmeter. If you did have a "microwave voltmeter" and stuck it on a transmission line, at that one point it would measure the superposition of both forward and travelling wave amplitudes.
Think of looking out at the ocean. There can be waves coming into shore, and other waves bouncing off of piers, rocks...the height of the water is a superposition of all those waves.
If you wanted the power gain, you would measure S21 and square it [S21²]. For example, if you had a "3 dB attenuator pad", you would measure its S21 magnitude to be approximately 0.707. If you wanted to know how much it attenuated power, you would then use Pout/Pin=(.707)²=0.5. In other words, a 3 dB pad drops the power by half.