Extracellular vesicles (EVs) are an important intercellular communication conduit for cells that have applications in precision therapy and targeted drug delivery. Small EVs, or exosomes, are a 30–150 nm phospholipid-encased subpopulation of EVs that are particularly difficult to characterize due to their small size and because they are difficult to isolate using conventional methods. In this review, we discuss some recent advances in exosome isolation, purification, and sensing platforms using microfluidics, acoustics, and size exclusion chromatography. We discuss some of the challenges and unanswered questions with respect to understanding exosome size heterogeneity and how modern biosensor technology can be applied to exosome isolation. In addition, we discuss how some advancements in sensing platforms such as colorimetric, fluorescent, electronic, surface plasmon resonance (SPR), and Raman spectroscopy may be applied to exosome detection in multiparametric systems. The application of cryogenic electron tomography and microscopy to understanding exosome ultrastructure will become vital as this field progresses. In conclusion, we speculate on some future needs in the exosome research field and how these technologies could be applied.