Acetylation is an increasing area of focus for cancer research as it is closely related to a variety of cellular processes through modulation of histone and non-histone proteins. However, broadly targeting acetylation threatens to yield nonselective toxic effects owing to the vital role of acetylation in cellular function. There is thus a pressing need to elucidate and characterize the specific cancer-relevant roles of acetylation for future therapeutic design. Acetylation-mediated protein homeostasis is an example of selective acetylation that affects a myriad of proteins as well as their correlated functions. We review recent examples of acetylation-mediated protein homeostasis that have emerged as key contributors to tumorigenesis, tumor proliferation, metastasis, and/or drug resistance, and we discuss their implications for future exploration of this intriguing phenomenon.