<p>Colorectal Cancer (CRC) is a heterogenous malignancy, attributed by a vast array of mutations that govern the adenoma-carcinoma sequence. The underlying molecular mechanism of CRC recurrence is diverse and complex, in which cancer stem cells (CSCs) remain a major determinant of therapy discontinuation and refractoriness. In contrast to reigning cytotoxic therapies in abolishing cancer cells, leveraging the cytodifferentiation approach offers an effective modality while sparing normal cells. The concept of differentiation therapy fosters from the notion that such cancer stem cells can be either reverted back to their lineage or terminally differentiated cancer cells upon exposure to differentiation inducing agents like All-trans retinoic acid (ATRA). Beyond driving cellular differentiation, ATRA mediates other cellular processes like cell cycle arrest, apoptosis, and abrogates metabolic plasticity, EMT and angiogenesis in cancer cells. These pleiotropic effects of ATRA in modulating the typical hallmarks of cancer and its therapeutic limitations are being studied since 1900s. Despite this, its mode of action and factors impeding its therapeutic effects have not been elucidated in detail and thus remains obscure. However, over the years, various molecular signatures and pathways implicated in the therapeutic effects of ATRA has been unravelled in pieces. In an attempt towards a better picture, the current review aims to highlight the molecular mechanism of ATRA in attenuating the hallmarks of CRC and the factors affecting its therapeutic efficacy from a holistic perspective.</p><p></p>