Controlling nanodomain morphology of nanostructured epoxy thermosets is critical to modulate the mechanical properties of the cross-linked matrix. In this contribution, we demonstrate that this can be achieved by using a suitable block copolymer containing an epoxy soluble block with the ability to react toward the epoxy system during curing. For this purpose we designed an epoxidized poly(styrene-b-isoprene-b-styrene) block copolymer incorporating amine-reactive functionalities (eSIS-AEP) in the epoxidized block as modifier for an epoxy system, which allowed the formation of nanostructured thermosets with controlled spherelike nanodomain morphology. The eSIS-AEP was obtained in two steps from poly(styrene-b-isoprene-b-styrene) (SIS) block copolymer by controlled epoxidation of the olefinic block followed by partial oxirane ring-opening reaction using 1-(2-aminoethyl)piperazine as nucleophile. Before the curing reaction it was observed that poly(styrene) blocks self-assembled to form ordered spherelike nanostructures in blends of eSIS-AEP with epoxy precursors. Since the amine-reactive moiety was incorporated to the block copolymer so that it could react toward diglicidyl ether of bisphenol A (DGEBA) at a similar temperature than the DGEBA/hardener reaction, the epoxy miscible block of eSIS-AEP (ePI-AEP) was able to react with DGEBA during curing. Once the cross-linked network was formed, the initially obtained spherelike nanodomains were preserved, indicating that no reaction-induced microphase separation of ePI-AEP subchains occurred. A completely different scenario was ascertained for epoxidized SIS block copolymer, which conducted to nonspherical nanodomains due to the uncontrolled epoxidized poly(isoprene) demixing process during the curing reaction. These results demonstrate the importance of the epoxy soluble block being reactive toward the epoxy precursors to control the morphology of the obtained nanostructure.