Nanotechnology in drug delivery involves the use of materials at nanoscale range to deliver therapeutic agents in a controlled manner at specific sites. Current treatment methodology involves chemotherapy or radiotherapy for the cancer treatment and is associated with lot of side effects due to off-target delivery. Nanomaterials can minimize the side effects to healthy cells and enable higher dose at the target site by selective uptake. The field of nanomedicine includes drug delivery, bioimaging, biosensors, and tissue engineering. The chapter highlights the contribution of nanotechnology to cancer theranostics. There are some definite factors associated with the interaction of nanoparticle at nano–bio interfaces. The effect of nanoparticle size, shape, topography, surface charge, chemical composition, and targeting moieties can modulate biological processes. Novel biologically synthesized nanomaterials are used to modulate the uptake mechanism and nanoparticle trafficking to overcome multidrug resistance. This chapter addresses the challenges and opportunities of nanotechnology in clinical applications with focus on novel approaches that add to our understanding of cancer therapeutics by addressing nano–bio interaction to discover an effective nanomedicine for cancer patients. © 2022 John Wiley & Sons, Inc. All rights reserved.