Intra-arterial (IA) drug delivery is often assumed to offer a decisive advantage over intravenous (IV) administration by concentrating drug at the target organ. In practice, this advantage rarely materializes: most IA infusions still miss the majority of the target, and randomized trials show little to no benefit over IV therapy for most indications. Retinoblastoma remains a notable exception, where superselective IA chemotherapy is now standard of care, proof that IA delivery can outperform IV when its underlying pharmacokinetics are properly addressed. Imaging is central to closing that gap. Real-time imaging of vascular territory and drug pharmakokinetics ensures the drug reaches the intended target before any pharmacologic strategy can help. Molecular imaging with Zr89-bevacizumab PET quantifies how far osmotic pretreatment, flow control, and venous occlusion each push first-pass extraction beyond passive IA infusion. Real-time imaging during doxorubicin delivery into the lingual artery further visualizes drug distribution as it happens, guiding the timing of transient venous flow arrest to maximize residence time in the target vasculature. Together with IA-specific formulations engineered for fast extraction rather than the prolonged circulation IV therapy depends on, this image-guided approach substantially increases tumor drug capture in preclinical models and suggests a path for extending IA's benefits, currently proven mainly for retinoblastoma, to other cancers and beyond.