The splicing of precursor messenger RNA (pre-mRNA) requires the precise cleavage and formation of multiple phosphodiester bonds in nascent pre-mRNA polymers in order to produce a protein coding message that can be properly translated by the ribosome. Despite the precision of this process, the spliceosome maintains considerable flexibility to include, or not include, defined segments in the final message, thus allowing for the production of diverse transcripts with distinct functions from a single gene sequence. The combination of control and flexibility displayed by the spliceosome, in conjunction with input from cis-acting sequences and trans factors, presents a unique opportunity for molecular intervention during gene expression. Various chemical agents have the capacity to alter the natural process of pre-mRNA splicing, thereby producing levels of splicing products different than those found under natural conditions. This approach has powerful therapeutic utility where mutation has caused certain splice variants to be under- or over-represented. The following chapter highlights the exceptional advances that have been achieved recently in splicing modulation with splice switching oligonucleotides (SSOs) and small molecules, the two leading therapeutic modalities in this field.