Comb-shaped amphiphilic polymers are rapidly emerging as an alternative approach to amphiphilic block copolymers for hydrophobic drug solubilization. These polymers consist of a homopolymer or copolymer backbone to which hydrophobic and hydrophilic pendant groups can be grafted resulting in a comb-like architecture. The hydrophobic pendants may consist of homopolymers, copolymers and other low-molecular weight hydrophobic structures. In this review, we focus on hydrophobically modified preformed homopolymers. Comb-shaped amphiphilic polymers possess reduced critical aggregation concentration values compared with traditional surfactant micelles indicating increased stability with decreased disruption experienced on dilution. They have been fabricated with diverse architectures and multifunctional properties such as site-specific targeting and external stimuli-responsive nature. The application of comb-shaped amphiphilic polymers is expanding; here we report on the progress achieved so far in hydrophobic drug solubilization for both intravenous and oral delivery.