<p>Protein lipidation and ubiquitination are two fundamental post-translational modifications that orchestrate protein localization, stability, and function. Beyond their independent roles, emerging evidence reveals a complex crosstalk between these modifications that profoundly shapes tumor biology. Lipidation promotes membrane anchorage and functional activation of key oncogenic drivers, whereas ubiquitination dynamically controls protein abundance through proteasomal degradation or signaling modulation. Their interplay regulates pivotal processes in cancer, including immune evasion, tumor microenvironment remodeling, metabolic reprogramming, invasion and metastasis, and uncontrolled proliferation. Mechanistically, lipidation can shield proteins from ubiquitin-mediated degradation or recruit deubiquitinases, while ubiquitination governs the turnover and activity of lipidation enzymes, together forming a dynamic antagonistic-synergistic network. Recent advances highlight the therapeutic promise of targeting this axis: inhibitors of NMTs, DHHC enzymes, and lipidation-dependent pathways, as well as ubiquitin-based technologies such as PROTACs, DUB inhibitors, and molecular glues, are being developed toward clinical translation. By integrating mechanistic insights with therapeutic innovation, this review underscores lipidation-ubiquitination crosstalk as a critical regulatory hub and potential dual-modification target for precision oncology.</p>