Colony-Stimulating Factor-1 Receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts. Mutations of CSF1R have been implicated in neurodegeneration, skeletal anomalies, and cancers. Activation of CSF1R by endogenous cytokine ligation to the ectodomain triggers the autophosphorylation of the intracellular tyrosine kinase domain, and thereafter, activation of several downstream pro-survival kinase cascades, including PI3K, ERK1/2, and JNK. The immunological role of CSF1R in regulating tumor-associate macrophages (TAMs) have been well-documented. TAMs harboring activated CSF1R release tumorigenic cytokines, which further deconditioning tumor microenvironment to a protumoral phenotype. Pharmacological inhibition of CSF1R has emerged as a promising antitumor strategy, with PLX3397 (pexidartinib) been approved by the FDA for the treatment of tenosynovial giant cell tumor in 2019. Research around developing novel small-molecule CSF1R inhibitors, as well as expanding their potential indications, have drawn numerous attentions thenceforward. Herein, we've comprehensively reviewed the latest progression of CSF1R inhibitors under clinical and preclinical studies. Key findings of CSF1R targeted therapies either as monotherapy or combinatorial therapy have also been discussed.