Since its first description in the early 19 century, the inferior fronto-occipital fascicle (IFOF) and its anatomo-functional features were neglected in the neuroscientific literature for the last century. In the last decade, the rapid development of in-vivo imaging for the reconstruction of white matter (WM) connectivity (i.e., tractography) and the consequent interest in more traditional ex vivo methods (post-mortem dissection) have allowed a renewed debate about course, termination territories, anatomical relationships, and functional roles of this fascicle. We reviewed the main current knowledge concerning the structural and functional anatomy of the IFOF and possible implications in neurosurgical practice. The IFOF connects the occipital cortex, the temporo-basal areas, the superior parietal lobule, and the precuneus to the frontal lobe, passing through the ventral third of subinsular WM of the external capsule. This wide distribution of cortical terminations provides multimodal integration between several functional networks, including language, non-verbal semantic processing, object identification, visuo-spatial processing and planning, reading, facial expression recognition, memory and conceptualization, emotional and neuropsychological behavior. This anatomo-functional organization has important implication also in neurosurgical practice, especially when approaching the frontal, insular, temporo-parieto-occipital regions and the ventricular system. In conclusion, the IFOF is the most extensive associative bundle of the human connectome. Its multi-layer organization reflects important implications in many aspects of brain functional processing. Accurate awareness of IFOF functional anatomy and integration between multimodal datasets coming from different sources has crucial implications for both neuroscientific knowledge and quality of neurosurgical treatments.