Nanomedicines have emerged as a potent anti-tumor strategy with tremendous progress. However, complex structure of integrating different or even opposing nanoproperties into one nanomedicine to improve overall delivery efficiency after intravenous injection hampers clinical translation. Cell membrane-coated biomimetic nanomedicines (CMC-BNs) have been considered as rationally designed next-generation nanomedicines with high therapeutic efficacy, among which blood cell-derived cellular nanosponges (CTI-005) and immunotherapeutic nanomedicines (CE120) have already completed investigational new drug (IND) applications for clinical trials. Whereas, we are conscious of many challenges that need to be addressed before CMC-BNs can move from laboratory studies to clinical applications in solid tumor theranostics, especially the limited intrinsic targeting ability that leads to insufficient tumor penetration and cellular internalization. To overcome the Achilles’ heel, we comprehensively summarize the current state-of-the-art in active targeting strategies, rational design and potential applications, aiming to figure out the potential future directions and provide insights for CMC-BNs clinical translation.