Pythium insidiosum, an Oomycetes member in Kingdom Straminipila, causes a life threatening  infection termed pythiosis, in hosts inhabiting tropical, subtropical, and temperate regions. Clinical manifestation in animals are located in subcutaneous site and gastrointestinal tract, whereas in humans are more frequently vascular and ocular sites. Human pythiosis has been reported, mainly, from Thailand.  Hosts with ocular involvement were immunocompetent and those with vascular type usually found in lower extremities with ascending blood vessel infection, had hematologic disorders i.e.thalassemia. Its severity depends on how far the organism disseminates toward the main arteries. Thus, an earlier diagnosis and treatment are essential to decrease the mortality rate. P. insidiosum possesses sparsely septated hyphae in the host tissue and in vitro, making the misdiagnosis a challenge. The majority of pythiosis cases are misdiagnosed as mycotic infections and unsuccessfully treated with antifungal drugs. Laboratory aid such as serology, i.e., immunodiffusion, ELISA have been developed. Diagnosis, collecting and transporting the specimen are important factors because of its low temperature susceptibility. Currently molecular approaches have been helpful for both diagnosis and culture identification. Using CoxII DNA sequences, it was possible to separate P. insidiosum into clades with better resolution that using the ITS1-2 region. Thermophilic Helicase DNA amplification and its SNPs provides the advantage to differentiate Pythium spp. from Entomophthorales, which cause similar subcutaneous infections. To treat these patients, a combination of amputation; itraconazole and terbinafine; and immunotherapy with P. insidiosum antigen (PIA) have been used as a practical approach, even though no standard protocol has been ever introduced. The efficacy of using PIA immunotherapy was about 50-60% by the assumption that immune response after therapy shifts the immune status of the host from a Th2 to a Th1. Very few information on  the pathogenesis and genomics, proteomics of P. insidiosum are available. Thus, more studies are still needed to advance our understanding of this unusual pathogen that addresses as a fungus but it is Protistal microbe.