Copyright © 2017 by The American Association of Immunologists, Inc. The tetraspanin CD151 is a marker of aggressive cell proliferation and invasiveness for a variety of cancer types. Given reports of CD151 expression on T cells, we explored whether CD151 would mark T cells in a hyperactivated state. Consistent with the idea that CD151 could mark a phenotypically distinct T cell subset, it was not uniformly expressed on T cells. CD151 expression frequency was a function of the T cell lineage (CD8 > CD4) and a function of the memory differentiation state (naive T cells < central memory T cells < effector memory T cells < T effector memory RA1 cells). CD151 and CD57, a senescence marker, defined the same CD282 T cell populations. However, CD151 also marked a substantial CD28+ T cell population that was not marked by CD57. Kinome array analysis demonstrated that CD28+CD151+ T cells form a subpopulation with a distinct molecular baseline and activation phenotype. Network analysis of these data revealed that cell cycle control and cell death were the most altered process motifs in CD28+CD151+ T cells. We demonstrate that CD151 in T cells is not a passive marker, but actively changed the cell cycle control and cell death process motifs of T cells. Consistent with these data, long-term T cell culture experiments in the presence of only IL-2 demonstrated that independent of their CD28 expression status, CD151+ T cells, but not CD1512 T cells, would exhibit an Ag-independent, hyperresponsive proliferation phenotype. Not unlike its reported function as a tumor aggressiveness marker, CD151 in humans thus marks and enables hyperproliferative T cells.