Transporters are involved in material transport, signaling, and energy input in all living cells. One of the fundamental questions about transporters is concerned with the precise role of their substrate in driving the transport process. This is particularly important for uniporters, which must utilize the chemical potential of substrate as the only energy source driving the transport. Thus, uniporters present an excellent model for the understanding of how the difference in substrate concentration across the membrane is used as a driving force. Local conformational changes induced by substrate binding are widely considered as the main mechanism to drive the functional cycle of a transporter; in addition, reducing the energy barrier of the transition state has also been proposed to drive the transporter. However, both points of view require modification to allow consolidation with fundamental thermodynamic principles. Here, we discuss the relationship between thermodynamics and kinetics of uniporters. Substrate binding-induced reduction of the transition-state energy barrier accelerates the transport process in kinetic terms, while the chemical potential of the substrate drives the process thermodynamically.