Since its approval 30 years ago, t-PA (and more recently its derivative, tenecteplase; TNK) remains the only thrombolytic treatment option for acute ischaemic stroke. Despite its efficacy, t-PA also carries notable shortfalls, emphasising the ongoing need to develop ground-breaking thrombolytic agents that are both efficacious and safe, and better methods for their delivery. New, smart fusion constructs, designed for targeted delivery of clot-dissolving enzymes via antibody-based clot recognition, hold promise for overcoming current shortcomings. Alongside other nanotechnological advancements for improved delivery of thrombolytic drugs in nanocarriers, and better approaches for co-delivery of combination therapies based on a ‘holistic’ view of the clot as a heterogeneous substance, these innovations may be finally able to deliver the long-awaited thrombolytic ‘magic bullet’ for stroke. This talk will describe several principles and approaches from our group and others that guide current research efforts for development of better thrombolytic treatment for ischaemic stroke.