How can we reopen blocked blood vessels quickly and safely when a clot forms in stroke, heart attack, deep-vein thrombosis, or pulmonary embolism? Current care relies on clot-dissolving drugs given through the bloodstream and catheter-based procedures that mechanically retrieve thrombi and/or deliver drugs locally. These methods can be lifesaving, but they are limited by residual distal microvascular obstruction, reduced efficacy against dense or lysis-resistant clots, and procedure-related complications such as hemorrhage and downstream embolization. This review compares 2 complementary technology paths: “tethered” catheter systems designed for rapid and operator-controlled reopening of large vessels, and “untethered” micro/nanoscale systems, including injectable carrier-based platforms and actively actuated micro/nanorobots, that can be actuated and guided by magnetic, ultrasound, or light energy to seek, penetrate, and disrupt clots at the microscale. Across reported studies, rationally engineered nanocarriers can improve clot targeting and local retention of thrombolytic payloads, while externally powered microrobots and microswarms enable active mixing and mechanical assistance, often reducing treatment time and lowering required drug doses in preclinical models. We further summarize imaging and tracking strategies that ensure feedback control of device position, energy delivery, and treatment endpoints. Finally, we discuss key translational barriers, including robust navigation under complex hemodynamics, reliable stopping and clearance, standardized safety windows, and seamless integration into established interventional workflows, thereby outlining actionable priorities that can steer this field toward clinical therapies.