By predicting the potential signal peptides from proteins that are naturally secreted by Pichia pastoris, we identified three possible endogenous signal peptides: Scw, Dse and Exg. We compared their capability to mediate the secretion of enhanced green fluorescent protein (EGFP) and Candida antarctica lipase B (CALB) with that of the Saccharomyces cerevisiae α-factor prepro-signal. EGFP entered the secretory pathway of P. pastoris and was efficiently secreted into the culture medium by all three endogenous peptides. Further, these three putative endogenous signal peptides were also effective in secreting CALB. These endogenous signal peptides thus have the potential to mediate the efficient secretion of heterologous proteins in P. pastoris.