One of the primary threats in tumor treatment revolves around the limited ability to penetrate tumor sites, leading to reduced therapeutic effectiveness, which remains a critical concern. Recently gaining importance are novel peptides, namely CRGDK/RGPD/EC (iRGD), that possess enhanced tumor-penetrating and inhibitory properties. These peptides specifically target and penetrate tumors by binding to αvβ integrins, namely αvβ3 and αvβ5, as well as NRP-1 receptors. Remarkably abundant on both the vasculature and tumor cell surfaces, these peptides show promising potential for improving tumor treatment outcomes. As a result, iRGD penetrated deep into the tumor tissues with biological products, contrast agents (imaging agents), antitumor drugs, and immune modulators after co-injecting them with peptides or chemically linked to peptides. The synthesis of iRGD peptides is a relatively straightforward process compared to the synthesis of other traditional peptides, and they significantly improved tumor tissue penetration inhibiting tumor metastasis effectively. Recent studies demonstrate the effectiveness of iRGD-driven dual-targeting chemotherapeutics on cancer cells, and the nanocarriers were modified with iRGD, serving as a favorable delivery strategy of payloads for deeper tumor regions. This review aims to provide an overview to emphasize the recent advancements and advantages of iRGD in treating and imaging various cancers.