Solid-state nanopore has the ability to detect proteins at a single-molecule level with its high sensitivity, high-throughput, and low cost. Improvements in fabrication, functionalization, and characterization of solid-state nanopores keep evolving. Various analytical methods targeted towards diagnostic applications using nanopore-based devices are appearing. This review article provides an overview of recent progress in the field of solid-state and biological nanopores for protein detection in a complex analyte. The advantages and challenges involved in nanopore sensing have been discussed. Further, the review surpasses the steady-state resistive pulse techniques of sensing and incorporate transient variations in the nanopore conductance. Application of the power spectral density of these fluctuations toward sensing has been highlighted with importance on reducing the detection limit in a complex environment. Lastly, the current problems and future perspectives have been discussed with a perspective to increase nanopores performance towards diagnostic applications in complex medium. Display omitted •Overview of recent developments of solid-state and biological nanopores for protein sensing in a complex analyte.•Functionalization strategies of both solid-state and biological nanopores.•Application of the power spectral density of transient nanopore conductance fluctuations in a complex environment.