Prostate cancer (PCa) is the second most common malignancy in men, and androgen deprivation therapy (ADT) is the first-line therapy. However, most cases will eventually develop into castration-resistant prostate cancer (CRPC) after ADT treatment. Enzalutamide (Enz) is a second-generation androgen receptor inhibitor approved by the Food and Drug Administration to treat patients with CRPC. Unfortunately, patients receiving Enz treatment will ultimately develop resistance via various complicated mechanisms. In this review, we introduce the emerging information on resistance mechanisms, including androgen receptor-related signalling pathways, glucocorticoid receptor-related pathways, and metabolic mechanisms. Notably, lineage plasticity and phenotype switching, gene polymorphisms, and the relationship between microRNAs and drug resistance are addressed. Furthermore, potential therapeutic strategies for Enz-resistant CRPC treatment are suggested, which can help in the discovery of more effective and specific regimens to overcome Enz resistance.