The highly regular orthographies (spelling systems) of many nations expedite literacy development, and their children experience a rapid transition from early literacy (learning to read and write) to sophisticated literacy (reading and writing to learn). In contrast, English orthographic complexity impedes literacy development, particularly for weak readers (Galletly & Knight, in press a, b). This article proposes a model of differential disadvantage of Anglophone weak readers due to cognitive processing weakness and the high cognitive load of learning to read and write English. The disadvantage is differential, first with Anglophone weak readers disadvantaged compared to weak readers in nations with regular orthographies, and second, with subgroups of Anglophone weak readers being more disadvantaged, depending on their levels of language skills and cognitive processing efficiency. Anglophone weak readers with pre-existing language disorder experience the highest levels of differential disadvantage. Weak cognitive processing and automisation in the face of continuing high cognitive load seems a basis for them frequently showing comorbidities, with features of multiple disorder categories (Catts, Adlof, Hogan, & Ellis Weismer, 2005), including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), auditory processing disorder, motor weakness, and social and behavioural impairment. The model is a useful framework for considering the instructional needs of weak readers. Areas where research is needed for building ways forward in optimising literacy development is discussed.