Two-dimensional (2D) layered materials with atomic- to nano-scale thickness have a wide variety of applications, one of which is as a solid lubricant. These materials have intrinsically low friction and good anti-wear properties, and thus are promising for a variety of emerging nanoscale technologies, but a fundamental understanding of their properties is not yet well-established. This dissertation seeks to address this from a nanoscopic point of view with atomistic simulations. First, through direct comparison of atomic-scale friction of monolayer graphene, monolayer MoS2, and a graphene/MoS2 heterostructure, we showed that graphene exhibits lower friction than MoS2, graphene, and their heterostructure. The origin of this friction contrast was shown to be the difference in surface energy barrier height (i.e., magnitude of the surface potential energy) due to the higher dispersion contribution to the sliding barrier for MoS2. We then isolated and understood the role of tip apex structure on the quality (i.e., distortion and degree of symmetry) of the surface energy landscape. In this context, we showed how different patterns of friction anisotropy can arise due to changes in quality of the tip–sample interfacial structure, an explanation that challenges previously proposed anisotropy mechanisms. Next, the effect of the elemental composition of 2D materials on single asperity friction was systematically explored by characterizing the friction and adhesion of MoS2, MoSe2, and MoTe2. We found that the presence of larger atoms within the lattice of a 2D material unexpectedly decreased friction. Our simulations and numerical analysis revealed that the lattice spacing, a parameter previously disregarded, significantly affected friction. Specifically, a larger lattice spacing due to the larger chalcogen enabled the tip to slide more easily across correspondingly wider saddle points in the potential energy landscape, resulting in lower friction. Finally, we used simulations to correlate the dynamics of a sliding contact to its electrical conduction. Both current and lateral force exhibited fluctuations corresponding to the periodicity of the substrate lattice, i.e., stick-slip, and the lateral force increased during stick events while the current decreased exponentially. We attributed this inverse correlation between current and lateral force to sliding-induced variations in atom–atom distances across the contact. Overall, the results of this dissertation contribute to establishing the framework of fundamental knowledge needed to design and optimize 2D materials for emerging applications.