The incessant transitions occurring in a cancer cell in response to cancer therapy have put forth a lot of irreversible consequences, eventuating a high mortality rate. This upsurge in morbidity and fatality is rationalized by the unilateral modes of conventional treatment regimens such as chemotherapy and radiation therapy. Eventually, the advent of nanotechnology in cancer medicine has unfolded a plethora of efficient ways to tackle the impediments associated with current treatment modalities such as metastasis, relapse, and therapy resistance. Active targeting guides nanocarriers for not just mitigating the drug payload but also minimizing the off-target side effects. Nanotherapeutics emphasizes this multidimensional approach and has portrayed promising preclinical outcomes, but clinical assessments need yet to be validated. This review discusses and elaborates on the oligonucleotide aptamer−nanoparticles leveraging active targeting and its applications in multifarious therapeutic interventions for the eradication of cancer. This, in combination with the various technological gains in aptamer synthesis, projects its potential contribution in the facet of nanomedicine. © 2020 American Chemical Society