Suboptimal cancer accumulation and low drug loading hinder the clinical translation and application of medicines in cancer therapy. Nanomedicines with valuable advantages, such as small particle size, high drug loading, and high active targeting ligand/efficiency to cancer are possible to accelerate the clinical translation process for cancer therapy applications. Compared with matrix-based nanodrugs, drug nanocrystals (NCs) possesses high drug loading, low carrier toxicity, and great structural stability, which makes it quite promising formulation or pharmaceutics for poorly water-soluble anticancer drugs. Many hydrophobic drugs were explored for drug NCs in cancer therapy, such as paclitaxel (PTX), docetaxel (DTX), camptothecin (CPT), and so on. However, uncontrolled premature leakage/dissolution, absence of active targeting, and easy clearance by the mononuclear phagocytosis system (MPS) lead to great obstacles to the clinical anticancer application of drug NCs. In recent years, functional modification-based strategies are applied to improve uncontrolled drug release and low targeting efficiency to cancer. Strategies including surface modification, nanocomplexes, biomimetic membrane coating, self-assembly, and drug synergy are highlighted in this review. Besides various advantages, challenges, and opportunities of these functional NCs in the clinical translation are also should be considered.