Erdheim Chester disease (ECD) is a rare type of non Langerhans cell histiocytosis [
1],[
2]. It is chiefly characterized by the migration and infiltration of lipid laden CD68(+), CD1a(-) histiocytes to various target organs resulting in the disruption of tissue architecture and fibrosis, thus causing impaired organ function and often bone pain [
3]. Among different individuals, this condition may manifest in a heterogeneous spectrum of severity ranging from a mild to a life threatening disease [
4]. Different patients may also present with an assortment of symptoms correlating with their specific sites of infiltration. However, up to 96% of patients exhibit radiological involvement of the skeleton [
5]. While
99mTc bone scintigraphy and positron emission tomography/computed tomography (PET/CT) are commonly used in the diagnosis of ECD, bone magnetic resonance imaging (MRI) may serve as a sensitive and valuable tool in the evaluation of cancellous bone involvement [
6]. Apart from the skeletal system, other sites of involvement include the central nervous system [
7]-[
11], heart and great vessels [
12]-[
15], lungs [
16]-[
18], kidneys and retroperitoneum [
19]-[
23], adrenal glands [
24], skin [
25]-[
27], gastrointestinal tract [
28]-[
31], breast [
32]-[
34], skeletal muscle [
32],[
35], thyroid and testis [
36]. Hemophagocytosis was also documented in the context of ECD [
37]. Involvements of the central nervous system (CNS) and cardiovascular systems, in particular, were reported to be associated with an overall poor prognosis [
38]. This is important to emphasize since the cardiovascular manifestations of ECD are frequently overlooked [
39]. Although the mean age of diagnosis among ECD patients is 55 [
5], pediatric cases have been documented [
40]-[
44]. To date, the etiology of ECD remains unknown and its pathogenesis, poorly understood. Much debate has arisen relating to the clonality of ECD [
45]-[
48]. On the one hand, it is well established that ECD is a phenomenon involving a dominant Th1 immune response, suggesting a dysregulated, inflammatory mechanism [
49]. On the other hand, the
V600E BRAF mutation recently identified in 54% of the patients [
50] necessitates a precursor cell harboring this somatic mutation and, thus, a clonal neoplastic origin. A novel approach is described by Berres
et al., who suggest that ECD is an example of an `inflammatory myeloid neoplasm’ [
51]. The fitting therapeutic roadmap for the ECD patient is a complex mosaic of various clinical elements [
52],[
53]. A diverse compilation of pharmacology has been under investigation over the past years in an attempt to strike at the Achilles heel of the disease. Currently, interferon-α is the sole agent which has demonstrated an increase in survival and is, thus, considered the first line of treatment [
14],[
38],[
54]-[
56]. Various second line treatments exist. Anakinra, an interleukin-1 receptor antagonist is suitable for mild disease [
13],[
40],[
57]-[
59]. Infliximab, an anti TNF-α monoclonal antibody has shown efficacy in the treatment of the cardiovascular involvement of ECD [
60]. Vemurafenib, a small molecule which inhibits the
V600E mutated
BRAF protein, was found to induce remarkable responses among patients who harbor that mutation [
61],[
62]. Finally, cladribine may be a reasonable therapeutic alternative for patients with moderate to severe disease who failed previous second line regimens [
63]-[
66]. Other treatments include various types of chemotherapeutic agents [
67]-[
70], radiation therapy [
71]-[
74], steroids [
38],[
54],[
70],[
75], bisphosphonates [
76]-[
78] and bone marrow transplantation [
79],[
80]. The prognosis of ECD is poor. Most patients suffer from progressive morbidity, which may relate to both the disease itself and its treatments. As for mortality, according to the largest series published, the one- and five-year survival rates of ECD patients are 96% and 68%, respectively [
38].