Mo–Si–B alloys have attracted considerable research interest during the last several decades due to their high melting points, excellent high-temperature strength and relatively good oxidation resistance. However, insufficient room-temperature fracture toughness and high-temperature oxidation resistance restrain their further application. Generally, a sufficient volume fraction of BCC-Mo solid-solution phase, providing the ductility, and a high Si content, responsible for the formation of passive oxide scales, is difficult to achieve simultaneously in this ternary system. Recently, macroalloying of Ti has been proposed to establish a novel phase equilibrium with a combination of enough BCC phase and intermetallic compounds that contain a large amount of Si. In this article, the development history from the ternary Mo–Si–B to the quaternary Mo–Ti–Si–B system was reviewed. It was found that the constitution phases could be easily tailored by changing the Ti content. In this regard, better performance of mechanical properties and oxidation resistance can be obtained through proper alloy design. In-depth understanding of the advantages of the quaternary alloys over their ternary ancestors may contribute to bringing about a new concept in designing novel ultra-high-temperature structural materials.