Salt stress is a severe threat to agricultural productivity in many parts of the world. Cotton (Gossypium hirsutum) is an economically important fiber crop globally, and is regarded as a model crop for salinity tolerance research. Although cotton is a relatively salt-tolerant plant, its growth and development, as well as fiber yield and quality, are greatly reduced by severe salt conditions. Salinity tolerance studies in cotton have focused on finding the key molecular genetic processes activated in response to salt stress, for breeding salt-tolerant cotton genotypes. In response to salt stress, cotton exhibits a variety of changes at the molecular, biochemical, and physiological levels. Photosynthetic pathways and metabolism play pivotal roles in redox balance and ion homeostasis. Several stress signaling pathways, for example, abscisic acid, salt overly sensitive (SOS), mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS), and membrane-bound Na+/H+ antiporters, all participate in salinity tolerance. The activation and regulation of specific genes drive this physiological and biochemical plasticity. In cotton, the roles of several transcription factors (for example, WRKY, ZFP, NAC, DREB, bZIP, and ERF) in salt stress tolerance have been well documented. We also highlight the potential areas for future investigation to elucidate the key pathways for effective breeding of salt-tolerant cotton genotypes.