Magnesium (Mg) based alloys are of interest in a wide variety of industries including automotive, aerospace, and electronic industries, in part because they possess a high strength-toweight ratio while being environmentally benign [1,2]. However, many applications of Mg alloys have been hindered by their low strength and poor plasticity at room temperature [3][4][5]. The poor plasticity of Mg stems from its highly anisotropic critically resolved shear stress of different slip systems [6,7]. As evidenced by recent experiments, basal slip initially takes place at the onset of plastic deformation on suitably oriented grains, followed by the gradual activation of prism and pyramidal slip systems under larger stress [6,8]. As such, plastic deformation of Mg and its alloys should arise from the combined influence of all slip systems, which include the basal 〈a〉, prism 〈a〉, pyramidal I (Py-I) 〈a〉, Py-I 〈c + a〉, and pyramidal II (Py-II) 〈c + a〉. Despite numerous published studies focus on alloying effects on the activation of slip systems, limited attention has been paid to the alloying effects on the activation probability of slip systems of Mg alloys.In this study, we carried out density functional theory (DFT) calculations to systematically investigate alloying effects on stacking fault energies associated with slip system activation, and activation rate of basal 〈a〉, prism 〈a〉, Py-I 〈a〉, Py-I 〈c + a〉 and Py-II 〈c + a〉 slip systems. We find that alloying solutes with atomic radius larger than that of Mg can reduce the stacking fault energy and increase activation rate of Py-II 〈c + a〉 slip system, and ultimately improve the plasticity of Mg. These findings provide a physical understanding of the effects of alloying on the