T-cell activation is the central event governing its development, differentiation, and effector functions. T-cell activation is initiated by the direct physical interaction of the T cell antigen receptor (TCR) with cognate peptide presented by the major histocompatibility complex (pMHC) molecule expressed on the antigen presenting cell (APC) surface. Since the identification of TCR as the only receptor for antigen on T cells three decades ago, studies have elucidated the major molecular players and signaling events responding to TCR stimulation. However, the question of how the physical event of pMHC binding is converted across the membrane into chemical events to initiate signal transduction remains elusive. Here we review recent investigations of T-cell activation using single-molecule force and fluorescence techniques that shed new light on this key question.