Cluster of differentiation 47 (CD47), an immune checkpoint commonly referred to as the “don’t eat me” signal, plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells (DCs). Although early enthusiasm drove broad clinical development, recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential. The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategies aimed at overcoming their limitations. Clinical challenges, including anemia, thrombocytopenia, suboptimal pharmacokinetics, and limited single-agent efficacy, underscore the need to develop safer, more selective approaches. Emerging next-generation strategies, such as SIRPα-directed agents, bispecific antibodies, and conditionally active therapeutics, are designed to enhance safety and tumor selectivity and reduce systemic toxicity. In addition, spatial profiling and biomarker-driven patient selection are advancing toward guiding rational therapeutic combinations, including with “eat-me” signals (e.g., calreticulin [CALR]) or DNA damage response therapies (e.g., poly(ADP-ribose) polymerase [PARP] inhibitors). Rather than signaling failure, these developments underscore the need for precision, context-specific applications, and adaptive trial designs to realize the durable therapeutic promise of CD47 blockade in cancer immunotherapy.