Integrins are Alpha-Beta transmembrane receptors that mediate cell-matrix and cell-cell adhesion, comprised of multi-domain, massive ectodomains, single-pass, transmembrane domains, and short, floppy cytoplasmic domains. They link the extracellular matrix or counter-receptors on other cells with the contractile cytoskeleton, mediating the transduction of mechanochemical signals across the plasma membrane and playing critical roles in a host of cellular functions, such as migration, cell traction, motility, platelet aggregation, and leukocyte transmigration. Functionally, integrins are switch-like proteins that can take on at least three different functional states: inactive, active, and ligand-bound. Integrin function is dependent upon allosteric conformational changes in its structure. Integrins are by default in an inactive (low affinity) state and can be activated via interacting with cytoplasmic proteins (e.g. talin) and/or engaging with extracellular ligands (e.g. fibrinogen). Integrin activation triggered by a cytoplasmic signal is called inside-out signaling, while outside-in signaling is defined as ligand-integrin binding followed by conformational changes in the transmembrane and cytoplasmic domains. Association of the integrin with the ligand induces quaternary changes in the integrin, leading to cell signaling and dynamic cell adhesion. However, atomistic details of these conformational changes as well as mechanisms of integrin clustering are not fully understood. This study employs molecular dynamics techniques to provide detailed, mechanistic answers for a few key questions on integrin (Alpha)IIb(Beta)3 function, a platelet-specific integrin member that plays a critical role in thrombosis. It is highly debated whether integrin transmembrane domains form homo-oligomers, leading to focal adhesion growth. This study suggests that homo- oligomerization of the Beta subunit potentially regulates integrin clustering, as opposed to the Alpha subunit, which appears to be a poor regulator for the clustering process. Two distinct hypotheses are proposed to explain the atomic mechanism of integrin activation and how conformational changes triggered by cytoplasmic/extracellular proteins are propagated across the integrin structure: The switch-blade and the deadbolt model. To reconcile these apparently-contradictory models for integrin activation, this work investigated the mechanism of integrin (Alpha)IIb(Beta)3 inside-out activation triggered by interactions with the cytoplasmic protein talin, and its outside-in activation as a result of exposure to the soluble RGD ligand. Finally, it was shown that the integrin Alpha subunit head domain regulates integrin-ligand binding affinity indirectly via inducing conformational changes in a key metal ion binding site (named LIMBS) in the Beta subunit head domain. Hence, it was concluded that different ligand binding affinities of integrin (Alpha)IIb(Beta)3 and (Alpha)V(Beta)3 is attributed to the larger attraction between the (Alpha)V subunit head domain and the metal ion binding site LIMBS.