Dyscalculia and mathematical learning disability (MD) are neurodevelopmental disorders characterized by difficulties in reasoning about numbers. Children with MD lag behind their typically developing peers in a broad range of numerical tasks, including magnitude judgement, quantity manipulation, arithmetic fact retrieval, and problem-solving. This chapter reviews current theories and knowledge of MD and its neurobiological basis from a systems neuroscience perspective. The chapter shows that MD involves processing deficits and aberrancies in multiple neurocognitive systems associated with non-symbolic and symbolic quantity judgment, visuo-spatial working memory, associative memory, and cognitive control. Convergent evidence from task and resting-state fMRI, along with morphometric and tractography studies, is used to demarcate distributed brain circuits disrupted in MD. The chapter examines neural mechanisms underlying intervention and remediation of deficits in MD, highlighting links between brain plasticity and response to treatment. The view that emerges is of a multi-component neurodevelopmental disorder, arising from aberrancies at one or more levels of the numerical information processing hierarchy.