INTRODUCTION: High-resolution imaging is the gold standard to measure the functional and biological features of bone lesions. Imaging markers have allowed the characterization both of tumour heterogeneity and metabolic data. Besides, ongoing studies are evaluating a combined use of "imaging markers", such as SUVs, MATV, TLG, ADC from PET and MRI techniques respectively, and several "biomarkers" spanning from chemokine immune-modulators, such as PD-1, RANK/RANKL, CXCR4/CXCL12 to transcription factors, such as TP53, RB1, MDM2, RUNX family, EZH2, YY1, MAD2. Osteoimmunology may improve diagnosis and prognosis leading to precision medicine in bone lesion treatment. Areas covered: We investigated modalities (molecular and imaging approach) useful to identify bone lesions deriving both from primary bone tumours and from osteotropic tumours, which have a higher incidence, prevalence and prognosis. Here, we summarized the recent advances in imaging techniques and osteoimmunology biomarkers which could play a pivotal role in personalized treatment. Expert Commentary: Although imaging and molecular integration could allow both early diagnosis and stratification of cancer prognosis, large scale clinical trials will be necessary to translate pilot studies in the current clinical setting.