CRISPR/Cas9 technology is a highly flexible RNA-guided endonuclease (RGEN) based gene-editing tool that has transformed the field of genomics, gene therapy, and genome/epigenome imaging. Its wide range of applications provides immense scope for understanding as well as manipulating genetic/epigenetic elements. However, the RGEN is prone to off-target mutagenesis that leads to deleterious effects. This review details the molecular and cellular mechanisms underlying the off-target activity, various available detection and prediction methodology ranging from sequencing to machine learning approaches, and the strategies to overcome/minimise off-targets. A coherent and concise method increasing target precision would prove indispensable to concrete manipulation and interpretation of genome editing results that can revolutionise therapeutics, including clarity in genome regulatory mechanisms during development.