The carcinogenesis process includes several epigenetic modifications that mainly target the silencing of tumor suppressor genes (TS genes) including ribonucleic acid (RNA) editing, deoxyribonucleic acid (DNA) hypermethylation and histone modification, either by methylation and demethylation, or acetylation and deacetylation. Histone deacetylation is one of the most important epigenetic modifications responsible for cancer development, and thereby, the design of new selective histone deacetylase inhibitors (HDACIs) is a promising chemotherapeutic target. Up to this time, all HDACIs approved are hydroxamic acid based. Yet, hydroxamic acids often show several drawbacks upon administration, such as poor pharmacokinetic properties, poor selectivity, and multiple toxicities. That's why the urge of emersion of a new category of compounds was crucial. Thereby, non-hydroxamate based compounds attracted widespread attention by being a part of several biologically active compounds as a safer alternative for hydroxamate based ones. In this mini-review, we aim to focus on several non-hydroxamate based HDACIs, specifically those used as anticancer agents, and the concept behind their development.