Sentence simplification aims to reduce the reading complexity of a sentence by incorporating more accessible vocabulary and sentence structure. In this chapter we examine the process of lexical substitution and particularly the role that word sense disambiguation plays in this task. Most previous work substitutes difficult words using a predefined dictionary. We present the challenges faced during lexical substitution and how it can be improved by disambiguating the word within its context. We provide empirical results which show that our method creates simplifications that significantly reduce the reading difficulty of the input text while maintaining its grammaticality and preserving its meaning.