Transporter proteins embedded in the cell membrane enable the cell to complete the basic functions of expelling waste and allowing the intake of nutrients, the efflux of harmful substances, and the directional pumping of various ions as energy storage media or information carriers, thus ensuring the survival, growth, and reproduction of living cells. Thus, transporters are the basic functional units that cells rely on to establish temporal and spatial order. Transporters driven by the electrochemical potential across the membrane are conventionally called secondary active transporters, and they comprise the most abundant class of transporters in cells. Do these versatile secondary active transporters share common structural features and transport mechanisms independent of specific structures? Why is the membrane potential often more important than the chemical potential for the functioning of secondary active transporters? How can differential chemical potential energy of ions such as ΔpH be coupled to conformational changes in transporters to drive the transport process? This chapter will discuss the common mechanism of secondary active transporters by using proton-driven MFS family members as examples. The structural features of this flagship family of secondary active transporters are well understood. In this context, we will focus on the principle of how the membrane-potential driving force induces conformational changes, how differential affinity energy can be used in energy coupling, and how the mechanisms of symporters and antiporters differ mechanistically. Furthermore, we will discuss the energy coupling mechanisms of various non-MFS transporter families including APC/LeuT, CPA/NhaA, and RND/AcrB to emphasize their mechanistic commonalities.