Many solid tumor types, such as pancreatic cancer, have a generally poor prognosis, in part because the delivery of therapeutic regimen is prohibited by pathological abnormalities that block access to tumor vasculature, leading to poor bioavailability. Recent development of tumor penetrating iRGD peptide that is covalently conjugated on nanocarriers' surface or co-administered with nanocarriers becomes a popular approach for tumor targeting. More importantly, scientists have unlocked an important tumor transcytosis mechanism by which drug carrying nanoparticles directly access solid tumors (without the need of leaky vasculature), thereby allowing systemically injected nanocarriers more abundantly distribute at tumor site with improved efficacy. In this focused review, we summarized the design and implementation strategy for iRGD-mediated tumor targeting. This includes the working principle of such peptide and discussion on patient-specific iRGD effect in vivo, commensurate with the level of key biomarker (i.e. neuropilin-1) expression on tumor vasculature. This highlights the necessity to contemplate the use of a personalized approach when iRGD technology is used in clinic.