Abstract: Protein lactylation modification represents an emerging post-translational protein modification that regulates protein function through the covalent attachment of lactate to protein lysine residues, thereby linking epigenetic regulatory mechanisms to cellular metabolic activities. Tumors pose severe threats to human health, with numerous studies and hypotheses attempting to elucidate their mechanisms of progression. Significant advances have been achieved in tumor biology research, both for the proteins within the tumors and for their genetic alterations, especially in the field of epigenetics. Histone lactylation provides an epigenetic perspective to explain the internal mechanisms of the malignant progression of tumors. Crucially, lactylation occurs not only on histones but also across diverse proteins, collectively influencing tumorigenesis and progression through transcriptional, translational, and post-translational regulation, while participating in broader physiological and pathological processes. In this review, we focus on lactylation's multifaceted associations with malignant progression in breast cancer, colorectal cancer, non-small cell lung cancer, and other malignancies, such as the promotion of glycolytic activity in tumor cells and the induction of the polarization tendency of M2-like features in macrophages in the tumor microenvironment. We also explore how current clinical practitioners can further expand therapeutic paradigms or pave the way for other therapeutic approaches to address the current oncological issues of radiation and chemotherapy tolerance.