The SAM pointed domain containing ETS transcription factor（SPDEF） is an important member of the E26 transformation-specific transcription factor family. SPDEF is initially identified in prostatic epithelium and considered to be involved in prostate development and prostate cancer progression. However，recent studies revealed that SPDEF is also expressed in the respiratory system. It is pretty crucial for the differentiation of airway epithelium，especially for the proliferation and metaplasia of goblet cells. Due to the importance of goblet cells in respiratory health，extended understanding of SPDEF function not only helps us to illuminate the mechanism of abnormal mucus secretion but also open new perspectives for the management of these related diseases. This review mainly focuses on the recent data which studied the role of SPDEF in goblet cell control，highlighting a novel profile of SPDEF as a new target in mucus secretion moderation.