Nanoparticle drug delivery systems have been used in the clinic since the early 1990s. Over the past decades, the field of nanomedicine has evolved alongside technological advancements to improve therapeutic delivery. Newer generations of nanoparticles have emerged, enabling new treatment modalities. In 2016, a review was published on the clinical landscape of nanoparticle delivery systems, highlighting over 25 FDA or EMA approved nanomedicines and over 45 other nanoparticle technologies in clinical trials. This update provides a three-year update on the current clinical landscape, highlighting newly approved nanomedicines, status updates on previous trials, and new technologies entering the clinic. Three nanomedicines have been approved since 2016: VYXEOS, Patisiran/ONPATTRO, and NBTXR3/Hensify. VYXEOS is a chemotherapy nanoparticle that delivers a synergistic ratio of two drugs, improving survival in acute myeloid leukemia. Patisiran/ONPATTRO is an siRNA-delivering nanoparticle approved for hereditary transthyretin amyloidosis, being the first RNAi therapeutic approved by the FDA. NBTXR3/Hensify is a hafnium oxide nanoparticle that enhances radiotherapy, approved for soft tissue sarcoma. These approvals demonstrate the growing clinical impact of nanoparticles. Over 75 new trials have begun for previously non-approved nanoparticles, and over 15 new nanoparticle technologies have entered clinical trials. The clinical landscape continues to expand with new trials and technologies, showing the potential of nanoparticles in improving human health. Challenges remain in translating nanoparticles into clinical practice, but the field continues to make breakthroughs. The review highlights the progress in nanoparticle drug delivery and the potential for future advancements.Nanoparticle drug delivery systems have been used in the clinic since the early 1990s. Over the past decades, the field of nanomedicine has evolved alongside technological advancements to improve therapeutic delivery. Newer generations of nanoparticles have emerged, enabling new treatment modalities. In 2016, a review was published on the clinical landscape of nanoparticle delivery systems, highlighting over 25 FDA or EMA approved nanomedicines and over 45 other nanoparticle technologies in clinical trials. This update provides a three-year update on the current clinical landscape, highlighting newly approved nanomedicines, status updates on previous trials, and new technologies entering the clinic. Three nanomedicines have been approved since 2016: VYXEOS, Patisiran/ONPATTRO, and NBTXR3/Hensify. VYXEOS is a chemotherapy nanoparticle that delivers a synergistic ratio of two drugs, improving survival in acute myeloid leukemia. Patisiran/ONPATTRO is an siRNA-delivering nanoparticle approved for hereditary transthyretin amyloidosis, being the first RNAi therapeutic approved by the FDA. NBTXR3/Hensify is a hafnium oxide nanoparticle that enhances radiotherapy, approved for soft tissue sarcoma. These approvals demonstrate the growing clinical impact of nanoparticles. Over 75 new trials have begun for previously non-approved nanoparticles, and over 15 new nanoparticle technologies have entered clinical trials. The clinical landscape continues to expand with new trials and technologies, showing the potential of nanoparticles in improving human health. Challenges remain in translating nanoparticles into clinical practice, but the field continues to make breakthroughs. The review highlights the progress in nanoparticle drug delivery and the potential for future advancements.