Single-molecule methods have revolutionized molecular science, but techniques possessing the bond-level structural sensitivity required for chemical problems—e.g. vibrational spectroscopy—remain difficult to apply in solution. This thesis describes a new approach, fluorescence-encoded infrared (FEIR) spectroscopy, that couples IR-vibrational absorption to a fluorescent electronic transition to achieve high-sensitivity vibrational detection in solution with conventional far-field optics. Our approach uses a double resonance scheme that first excites vibrations by resonant IR absorption, followed by an electronically pre-resonant visible excitation (‘encoding’) that selectively brings the molecule to its fluorescent excited state. Femtosecond IR and visible pulses are used to make these transitions coincident within the picosecond vibrational lifetime, while splitting the IR pulse into a pulse-pair with an interferometer enables Fourier transform measurements of FEIR vibrational spectra. An FEIR instrument is described that combines design principles of ultrafast IR spectroscopy with single-molecule fluorescence microscopy to achieve high detection sensitivity. Specifically, a trade-off in repetition-rate between the requirements of efficient fluorescence photon counting and intense, femtosecond mid-IR pulse generation is satisfied by employing a 1 MHz Yb fiber laser to pump the experiment, and the IR pulse delivery is integrated into a confocal fluorescence microscope configuration. FEIR correlation spectroscopy, an IR-vibrational analogue of fluorescence correlation spectroscopy, is introduced to demonstrate single-molecule sensitivity in solution. Potential applications of this method as a vibrational probe of dynamic solution-phase chemical processes are proposed. The role of FEIR resonance conditions and other practical experimental factors in achieving single-molecule sensitivity are discussed through a comparative study of coumarin fluorophores. To aid in understanding the spectroscopic information content of FEIR experiments, a theoretical description based on fourth-order response functions for the electronic excited population is developed. Incorporating the effect of finite pulses and inter-mode vibrational coherence explains the appearance and encoding-delay dependence of FEIR signals in our measurements. Polarization-dependent FEIR experiments that probe the relative orientation of the vibrational and electronic transitions, as well as the manifestation of vibrational relaxation phenomena in FEIR signals, are discussed.