A simple route for the design of hydrophilic microgels comprising inner hydrophobic nanodomains has been developed based on postmodification of microgels by complexation of wedge-shaped amphiphilic molecules with complementary functional groups. Aqueous microgels functionalized with imidazole groups were transferred into an organic medium, where imidazole groups were neutralized by water-insoluble wedge-shaped molecules bearing a sulfonic acid group at the tip of the wedge and a large hydrocarbon body. After redispersion of the modified microgel particles into the aqueous phase, wedge-shaped amphiphiles ionically attached to the polymer chains self-assembled into discrete nanodomains in the interior of the polymer colloids due to the hydrophobic attraction force. The loading of the wedge-shaped molecules into microgels can be controlled by variation of the amount of imidazole groups integrated into the microgel network as well as the neutralization degree. The experimental results suggested that incorporation of hydrophobic domains into hydrophilic colloids induced dramatic changes of their properties such as swelling degree, surface charge, and responsiveness toward temperature and pH. Finally, we demonstrated that internally hydrophobized microgel particles are very effective in uptake of hydrophobic molecules in aqueous media.