In this review, we will discuss our recent approaches for the formation of mechanically stable bilayer lipid membranes (BLMs) by combining with BLM formation and micro- and nano-fabrication techniques. BLMs were prepared across a microaperture fabricated in silicon (Si) chips or nanoporous alumina films using a minimized amount of organic solvent. Although BLMs spanned over the porous alumina film showed better electrical properties, such as background current noise and current transient, BLMs suspended in a thin Si3N4 septum showed a much superior BLM stability. The BLMs showed tolerance to a high voltage of ±1 V, a membrane lifetime of >40 h, and tolerance to repetitive solution exchanges. Application to a drug screening system has been examined by using the human ether-a-go-go-related gene (hERG) potassium channel as an illustrative example. The potentiality of the present system as a platform of the high-throughput analysis for ion-channel protein is also discussed.