This chapter focuses on the spray-based methods for generating gas phase ions, a distinctive approach characterized by the gentle nature of the ionization process. No high energy external sources are needed for spray-based methods. As a result, it can produce intact molecular ions without fragmentation across a wide range of molecules, from small compounds to large biomolecules. This feature has facilitated their extensive use in mass spectrometry for analyzing complex biological samples and opens possibilities for many new domains of applications. This chapter begins with a brief historical overview of ion generation from liquid droplets in the air. It then discusses the underlying principles of the most widely used spray-based technique, such as electrospray ionization (ESI). In addition to ESI, other ambient spray-based ionization methods, including solid substrate ESI, desorption electrospray ionization (DESI), sonic spray ionization, and mechanical-based ionization methods, are discussed. These methods expand the versatility of spray-based ionization for various analytical applications.