Objectives Calcium-dependent protein kinases (CDPKs) function directly in plant development and stress responses. We used whole genome sequences and mRNA expression data to analyze the phylogenetic relationships, gene structure, collinearity, and differential expression of CDPKs in two differentially drought-tolerant potato varieties. Results In total, we identified 25 CDPK proteins belonging to four subfamilies. There was a significant collinear relationship among 13 CDPK genes belonging to four segmentally duplicated pairs. Subcellular prediction implied that all StCDPKs were localized at the plasma membrane. Analysis of promoter regions revealed that StCDPKs were photosensitive and responsive to biotic stress, abiotic stress, and hormone stimuli. RNA-seq analysis showed differential expression of StCDPKs among various potato tissues, and qPCR analysis revealed that 20 StCDPKs exhibited differential expression patterns under drought stress between drought-tolerant (QS9) and drought sensitive (Atl) potato varieties. Among these, the most strongly drought-induced genes were respectively StCDPK3 and StCDPK23, highlighting these as attractive candidate genes for further functional analyses of drought-stress responses in potato. Conclusions Our results demonstrating the tissue specific and drought stress-responsive StCDPK genes of potato both provide a reference for further research about the functions of CDPK family proteins and should support ongoing efforts for the further genetic improvement of potato.