Paediatric mature B-cell non-Hodgkin lymphoma (B-NHL) is a highly aggressive disease with one of the fastest growth rates of any human malignancy. The subtypes are Burkitt and Burkitt-like lymphoma/leukaemia, diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma; with Burkitt lymphoma/leukaemia alone accounting for 38% of NHL diagnoses in patients under 15 years. Outcomes have improved significantly in recent years with the introduction of intensive multi-agent chemotherapy, followed by the addition of Rituximab, resulting in a survival rate exceeding 90%. Despite this, those patients who acquire resistance to chemotherapy and/or Rituximab have a dismal prognosis with few salvage therapy options. The aim of this thesis was to identify cell populations that are driving therapy resistance in order to develop targeted treatments for relapsed and therapy-refractory patients. Utilising samples obtained from patients enrolled to the Inter-B-NHL ritux 2010 clinical trial, we established 5 paediatric Patient Derived Xenografts (PDXs) – to our knowledge the largest paediatric B-NHL resource of this type. These PDXs faithfully recapitulate tumour characteristics through passage and enable the identification of heterogeneous populations within these malignancies. One such population, known as the side population (SP), exhibits tumour initiating potential, expresses stemness-related genes and shows increased resistance to chemotherapy. In vitro, the SP produces soluble factors necessary for growth of the main population (MP) of cells (depleted of SP); indeed, MP and SP produce different cytokine profiles suggestive of cross-talk between the populations to maintain tumour cell growth. Furthermore, the PI 3-Kinase (PI3K) pathway was shown to be an important regulator of SP survival by regulating ATP-binding cassette (ABC) transporters hinting towards future therapeutic applications. Due to the rarity of biopsy samples taken at relapse in paediatric B-NHL, resistance to chemotherapy was induced both in vivo and in vitro mimicking relapse. In vivo, this was achieved by administering multi-agent chemotherapy over an extended period to mice bearing established PDX tumours until apparent cure. The subsequent relapsed tumours contain a significantly increased proportion of SP cells and RNA sequencing identified PI3K and B cell receptor pathways as potential therapeutic targets in a subset of chemo-resistant tumours. In order to identify further protein targets for the treatment of paediatric B-NHL that is resistant to standard chemotherapeutic agents including Rituximab, a CRISPR/Cas9-based genome-wide overexpression screen (SAM) was conducted with the human Burkitt Lymphoma cell line Raji. The screen and subsequent validation highlighted several potential therapeutic targets including proteins in the PI3K, MAP kinase and Toll-Like receptor (TLR) signalling pathways, with different mechanisms of resistance identified between cells treated with standard chemotherapy drugs or Rituximab. Overall, this thesis describes data showing that paediatric B-NHL consists of heterogeneous populations of tumour cells, including tumour initiating SP cells and MP progeny. The SP has significantly increased resistance to chemotherapy and supports the growth and survival of the MP through production of soluble factors with the PI3K pathway important in driving the SP phenotype. Furthermore, using both in vivo and in vitro models of resistance we have identified pathways that may be therapeutic targets in relapse/refractory disease.