Cryptomonads are complex microalgae which share characteristics of chromophytes (chlorophyll c, extra pair of membranes surrounding the plastids) and rhodophytes (phycobiliproteins). Unlike chromophytes, however, they contain a small nucleus-like organelle, the nucleomorph, in the periplastidial space between the inner and outer plastid membrane pairs. These cellular characteristics led to the suggestion that cryptomonads may have originated via a eukaryoteeukaryote endosymbiosis between a phagotrophic host cell and a unicellular red alga, a hypothesis supported by rRNA phylogenies. Here we characterized cDNAs of the nuclear genes encoding chloroplast and cytosolic glyceraldehyde-3-phosphate dehydrogenases (GAPDH) from the two cryptomonads Pyrenomonas salina and Guillardia theta. Our results suggest that in cryptomonads the classic Calvin cycle GAPDH enzyme of cyanobacterial origin, GapAB, is absent and functionally replaced by a photosynthetic GapC enzyme of proteobacterial descent, GapCl. The derived GapCl precursor contains a typical signal/transit peptide of complex structure and sequence signatures diagnostic for dual cosubstrate specificity with NADP and NAD. In addition to this novel GapCl gene a cytosol-specific GapC2 gene of glycolytic function has been found in both cryptomonads showing conspicuous sequence similarities to animal GAPDH. The present findings support the hypothesis that the host cell component of cryptomonads may be derived from a phototrophic rather than a organotrophic cell which lost its primary plastid after receiving a secondary one. Hence, cellular compartments of endosymbiotic origin may have been lost or replaced several times in eukaryote cell evolution, while the corresponding endosymbiotic genes (e.g., GapC1) were retained, thereby increasing the chimeric potential of the nuclear genome.