This article provides a comprehensive overview of the current treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) following the failure of first-line therapy. Although significant progress has been made in the primary treatment of hormone-sensitive prostate cancer, the management of mCRPC remains a clinical challenge. The article outlines the diagnostic criteria for mCRPC, which can be confirmed through biochemical progression and imaging techniques. Various drug classes are available for the treatment of mCRPC after first-line therapy failure, including androgen receptor signaling pathway inhibitors (ARPI), chemotherapeutics such as docetaxel and cabazitaxel, as well as newer agents like poly(ADP-ribose) polymerase (PARP) inhibitors and prostate-specific membrane antigen (PSMA)-based radioligand therapies. These agents are used as monotherapy or in combination, depending on the patient's status and treatment history. Choosing the appropriate follow-up therapy after first-line failure is often difficult because current study results are mostly based on older treatment concepts. Precise, molecular-based treatment planning could play a key role here. Molecular markers such as BRCA 1/2 mutations and imaging techniques like PSMA-PET/CT can help identify the most suitable therapy for individual patients. For example, patients with BRCA 1/2 mutations may benefit from a combination of PARP and ARPI therapy, while those with high PSMA levels may be considered for PSMA radioligand therapy. Thus, therapeutic options for the treatment of mCRPC are now diverse and promising, with the challenge being to determine the right sequences and combinations based on the individual patient profile.