Recent advances in pharmacology and a better understanding of underlying diseases have established a strong correlation between gene expression and diseases, revolutionizing the identification of therapeutic targets and their management [1,2]. Therefore, mRNA, an intermediate molecule, has become a target of interest [3]. mRNA is a messenger molecule that regulates all transcriptional and post-transcriptional processes. mRNA's property of complementary base pairing to itself or other molecules presents a tool to modify its splicing, translation, or abundance for treating diseases [4,5]. Oligonucleotide technology has been developed to specifically downregulate, upregulate, or modify critical gene expression in terminal illnesses, such as cancer or genetic disorders [6,7]. It has broadened the spectrum of potential therapeutic targets. By controlling the protein expression by RNA interference, proteins that were previously unaffected by conventional small molecules can be affected [8]. These therapeutics include antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), antimiR, and antagomiR [9,10]. In this review, we will specifically focus on ASOs. They are clinically recognized entities with several drugs approved by the United States Food and Drug Administration (FDA) and many in clinical trials. ASOs are single-stranded, chemically modifiable short nucleic acid sequences usually in the range of 18–25 bases in length [11]. On binding complimentarily to RNA sequences through Watson–Crick base pairing, they modulate or regulate the functions of pre-messenger ribonucleic acid (pre-mRNA) and mature mRNA (sense) [12]. These properties make ASOs a valuable addition to modern medicine with a high target specificity. It also addresses the concerns of previously undruggable or inaccessible targets. Hence, ASOs play the following roles in the modern therapeutic paradigm: (a) enhanced therapeutic access to undruggable diseases that lack treatment options; (b) the development of a new personalized medicine; (c) swift responses to new global health concerns, such as COVID-19, in which mRNA vaccines were quickly developed.