The article reviews recent advances in targeted drug delivery to tumors, focusing on the use of molecular markers in tumor vasculature as primary targets and nanoparticles as delivery vehicles. Tumor cells express various cell surface and extracellular matrix proteins that are not expressed or are expressed at much lower levels in normal cells, making them suitable for targeted delivery. The authors discuss the advantages of targeting tumor vessels over tumor cells, as tumor vessels are more accessible and do not require tissue penetration. They highlight the use of phage display and other unbiased methods to identify vascular markers, such as nucleolin, annexin I, and plectin-1. The article also explores the role of adhesion receptors and fibrin-fibronectin complexes in tumor targeting. Additionally, it covers the challenges of receptor capacity, monovalent versus multivalent binding, and the stability of targeting probes. The authors introduce tumor-penetrating peptides, such as iRGD, which can enhance drug delivery into tumor tissue. They discuss the limitations of synaptic targeting, including receptor capacity and the stability of targeting probes, and propose solutions like multivalent binding and tumor-penetrating peptides. The article concludes by emphasizing the potential of tumor-penetrating nanosystems to improve drug delivery and therapeutic outcomes in cancer treatment.The article reviews recent advances in targeted drug delivery to tumors, focusing on the use of molecular markers in tumor vasculature as primary targets and nanoparticles as delivery vehicles. Tumor cells express various cell surface and extracellular matrix proteins that are not expressed or are expressed at much lower levels in normal cells, making them suitable for targeted delivery. The authors discuss the advantages of targeting tumor vessels over tumor cells, as tumor vessels are more accessible and do not require tissue penetration. They highlight the use of phage display and other unbiased methods to identify vascular markers, such as nucleolin, annexin I, and plectin-1. The article also explores the role of adhesion receptors and fibrin-fibronectin complexes in tumor targeting. Additionally, it covers the challenges of receptor capacity, monovalent versus multivalent binding, and the stability of targeting probes. The authors introduce tumor-penetrating peptides, such as iRGD, which can enhance drug delivery into tumor tissue. They discuss the limitations of synaptic targeting, including receptor capacity and the stability of targeting probes, and propose solutions like multivalent binding and tumor-penetrating peptides. The article concludes by emphasizing the potential of tumor-penetrating nanosystems to improve drug delivery and therapeutic outcomes in cancer treatment.