In this work we review novel strategies and new physical effects to achieve compositional and structural recognition at single molecule level. This chapter is divided in two main parts. The first one introduces the strategies currently adopted to investigate matter at few molecules level. Exploiting the capability of surface plasmon polaritons to deliver optical excitation at nanoscale, we introduce a technique relying on a new transport phenomenon with chemical sensitivity and nanometer spatial resolution. The second part describes how micro and nanostructured superhydrofobic textures can concentrate and localize a small number of molecules into a well-defined region, even when only an extremely diluted solution is available. Several applications of these devices as micro- and nano-systems for high-resolution imaging techniques, cell cultures and tissue engineering applications are also discussed.