In this chapter, we describe the advances in high-resolution and tandem mass spectrometry applied for structural analysis of complex molecular systems. Focus is made on Fourier transform mass spectrometers (FTMS) because of their ability to routinely provide resolving power (resolution), which is above 100 000, and correspondingly high mass accuracy, which is higher than 2 ppm. The advantages of using these analytical capabilities have been demonstrated for analysis of extremely complex mixtures of molecules of diverse nature and size. What are the recent and envisioned steps in FTMS method and technique development? What are the novel application areas that await these developments? We describe the state-of-the-art in ion cyclotron resonance (ICR) and Orbitrap FTMS and showcase the advantages of FTMS applications for petroleomics and intact protein mass measurements. We briefly overview the current methods of ion activation and dissociation as most widely employed in tandem mass spectrometry (MS/MS) for peptide and protein structure analysis. Finally, we discuss the analytical limitations of the state-of-the-art FTMS and offer a brief introduction to some of the possible solutions to these limitations. Particularly, we describe the achieved and envisioned benefits of advanced signal processing methods aimed specifically at FTMS improvement.