This review outlines recently developed Prussian blue nanoparticle (PB NPs)-based multimodal imaging-guided chemo-photothermal strategies for cancer diagnosis and treatment in order to provide insight into the future of the field. The primary limitation of existing therapeutics is the lack of selectivity in drug delivery: they target healthy and cancerous cells alike. In this paper, we provide a thorough review of diverse synthetic and surface engineering techniques for PB NP fabrication. We have elucidated the various targeting approaches employed to deliver the therapeutic and imaging ligands into the tumor area, and outlined methods for enhancement of the tumor ablative ability of the NPS, including several important combinatorial approaches. In addition, we have summarized different in vitro and in vivo effects of PB NP-based therapies used to overcome both systemic and tumor-associated local barriers. An important new approach – PB NP-based immune drug delivery, which is an exciting and promising strategy to overcome cancer resistance and tumor recurrence – has been discussed. Finally, we have discussed the current understanding of the toxicological effects of PB NPs and PB NP-based therapeutics. We conclude that PB NP-based multimodal imaging-guided chemo-photothermal therapy offers new treatment strategies to overcome current hurdles in cancer diagnosis and treatment.