Metastatic castration-resistant prostate cancer (mCRPC) is a prevalent malignancy marked by molecular heterogeneity, which contributes to resistance to standard therapies and poor clinical prognosis. Advances in genomic and transcriptomic profiling have identified key drivers such as alterations in AR, TP53, PTEN, and RB1, which also enable cancer cells to circumvent therapies. Despite such advances, the underlying mechanisms involved in mCRPC drug resistance are complex, creating an urgent need for novel therapies to improve clinical outcomes. To address this clinical problem, strategies focused on targeting underlying molecular and metabolic supportive pathways using nano-delivery systems of diverse drugs could be promising in both CRPC and mCRPC therapy. This review provides an overview of the current understanding of the genomic and microenvironmental landscape of mCRPC and explores emerging classification frameworks aimed at improving patient outcomes. We highlight the potential of integrative multi-omics approaches to inform precision oncology and guide the development of more effective, personalized treatments for prostate cancer therapy.